molecules
Re iew
Cannabinoid Ac ions on Neu al S em Cells:
Implica ions o Pa hophysiology
Rui S. Rod igues 1,2,† , Diogo M. Lou enço 1,2,† , Sa a L. Paulo 1,2 , Joana M. Ma eus 1,2 ,
Miguel F. Fe ei a 1,2, F ancisco M. Mou o 1,2, João B. Mo ei a 1,2 , Filipa F. Ribei o 1,2,
Ana M. Sebas ião1,2 and Sa a Xapelli 1,2,*
1Ins i u o de Fa macologia e Neu ociências, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa,
1649-028 Lisboa, Po ugal; [email p o ec ed] (R.S.R.);
[email p o ec ed] (D.M.L.); [email p o ec ed] (S.L.P.);
[email p o ec ed] (J.M.M.); jo ge. e [email p o ec ed] (M.F.F.);
[email p o ec ed] (F.M.M.); [email p o ec ed] (J.B.M.);
[email p o ec ed] (F.F.R.); [email p o ec ed] (A.M.S.)
2Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa,
Lisboa, 1649-028 Lisboa, Po ugal
*Co espondence: [email p o ec ed]; Tel.: +351217985183
† These au ho s con ibu e equally.
Recei ed: 19 Ma ch 2019; Accep ed: 3 Ap il 2019; Published: 5 Ap il 2019


Abs ac :
Wi h he inc ease o li e expec ancy, neu odegene a i e diso de s a e becoming no only a
heal h bu also a social bu den wo ldwide. Howe e , due o he mul i ude o pa hophysiological
disease s a es, cu en ea men s ail o mee he desi ed ou comes. The e o e, he e is a need o
new he apeu ic s a egies ocusing on mo e in eg a ed, pe sonalized and e ec i e app oaches.
The p ospec o using neu al s em cells (NSC) as egene a i e he apies is e y p omising, howe e
se e al issues s ill need o be add essed. In pa icula , he po en ial ac ions o pha macological agen s
used o modula e NSC ac i i y a e highly ele an . Wi h he ongoing discussion o cannabinoid usage
o medical pu poses and epo s d awing a en ion o he e ec s o cannabinoids on NSC egula ion,
he e is an eno mous, and ye , unco e ed po en ial o cannabinoids as ea men op ions o se e al
neu ological diso de s, speci ically when combined wi h s em cell he apy. In his manusc ip , we
e iew in de ail how cannabinoids ac as po en egula o s o NSC biology and hei po en ial o
modula e se e al neu ogenic ea u es in he con ex o pa hophysiology.
Keywo ds: cannabinoids; neu al s em cells; neu ogenesis; egene a ion; pa hophysiology
1. In oduc ion
The de elopmen o a mul icellula o ganism can be compa ed o a cho eog aphed dance o
cellula and molecula in e ac ions in ol ing cell eo ganiza ion du ing p ecise s ages. Al hough in
mos egions o he mammalian b ain he p oduc ion o neu ons is la gely con ined o he p ena al
pe iod, in speci ic b ain egions, neu ogenesis occu s pos na ally and con inues in o adul hood.
In he mammalian cen al ne ous sys em (CNS), neu al s em cells (NSCs) a e cha ac e ized by
hei sel - enewal capabili y and mul ipo ency, i.e., he abili y o gi e ise o bo h neu ons and glial
cells, such as oligodend ocy es and as ocy es. A “neu ogenic niche” can be de ined as a complex
mic oen i onmen ha suppo s NSCs and hei p ogeny, helping o de e mine whe he NSCs emain
do man o di ide, by p o iding signals ha guide ea ly s ages o p oli e a ion o di e en ia ion.
One o hese signals has been shown o come h ough he ac ion o endocannabinoids (eCBs), mainly ia
ac i a ion o cannabinoid ecep o s ype 1 and 2 (CB1R and CB2R). Cannabinoid esea ch has been
Molecules 2019,24, 1350; doi:10.3390/molecules24071350 www.mdpi.com/jou nal/molecules
Molecules 2019,24, 1350 2 o 59
cap u ing he in e es o physicians, esea che s, pha maceu ical companies and o he gene al
popula ion wo ldwide because o i s b oad ange o applica ions. Impo an ly, inc easing da a has
been showing an impo an ole o cannabinoids in NSC modula ion, which migh allow combining
hei wide ange o ac ions wi h he mul i ude o applica ions ha s em cells o e .
In his e iew, we p o ide a summa y o cannabinoid ac ions and i s e ec s in NSC modula ion
bo h in de elopmen and in he adul b ain, highligh ing he ole o cannabinoids in pa hophysiology
and as he apeu ic agen s o neu o egene a ion.
2. Endocannabinoid Sys em and Cannabinoids
Cannabis has long been used by humans due o i s he apeu ic alue, o ec ea ional and eligious
pu poses, o p oduce ood o li es ock and, o i s ibe s, o manu ac u e clo hing [
1
]. Nowadays,
a g owing body o scien i ic e idence has been a es ing he immense po en ial o his plan o
amelio a e symp oms o se e al diseases. Indeed, medical-cannabis is being used o p oposed o ea
neu opa hic pain and muscle spas ici y associa ed wi h mul iple scle osis (MS), neu ode elopmen al
o ms o e ac o y epilepsy, neu odegene a i e and ch onic diseases [
1
–
10
]. Addi ionally, he e is
s ong scien i ic suppo o i s use in ea ing diso de s, o educe omi ing and nausea associa ed
wi h chemo he apy, and o alle ia e human immunode iciency i us in ec ion and acqui ed immune
de iciency synd ome (HIV/AIDS) ela ed weigh loss [1].
On he o he hand, ch onic consump ion o he apeu ic exposu e o cannabis can be ela ed
wi h de imen al heal h e ec s. Speci ically, hea y and sus ained cannabis use is associa ed wi h
cogni i e and memo y impai men s, inc eased p obabili y o de eloping schizoph enia-spec um
diso de s, acu e psychosis and mania [
11
–
15
]. Regula cannabis abuse can esul in ch onic b onchi is
and impai ed espi a o y unc ion i consumed h ough inhala ion. I can also induce physical and
signi ican men al dependence, ole ance and wi hd awal symp oms [
1
,
16
]. The e o e, one o he
challenges o cannabis esea ch is o ind ways o p e en he nega i e side-e ec s associa ed wi h
cannabis-based medicines [17,18].
Acco ding o he Wo ld D ug Repo 2017, ma ijuana (d ied lea es, lowe s, s ems and seeds
om he Cannabis sa i a o Cannabis indica plan s) is consumed by up o 238 million people
wo ldwide, making i , by a , he mos widely used d ug [
19
]. The psychoac i e e ec s o cannabis
consump ion include eupho ia, appe i e s imula ion, seda ion, al e ed pe cep ion, impai men s in
mo o con ol and memo y de ici s [
20
]. These e ec s a e almos exclusi ely ela ed wi h he p esence
o
∆9
- e ahyd ocannabinol (
∆9
-THC), which was i s ly isola ed in i s pu e o m and s uc u ally
desc ibed in 1964 [
21
]. Rega dless o i s psychoac i e e ec s,
∆9
-THC has he apeu ic alue and unique
applica ions [22].
Mo e han 120 phy ocannabinoids (na u al occu ing cannabinoids) ha e now been iden i ied
as cons i uen s o he cannabis plan [
23
]. Besides
∆9
-THC, he mos abundan cannabinoids p esen
in he cannabis plan a e
∆8
- e ahyd ocannabinol (
∆8
-THC), cannabinol (CBN), cannabidiol (CBD),
cannabige ol (CBG), cannabich omene (CBC),
∆9
- e ahyd ocannabi a in (THCV), cannabi a in (CBV)
and cannabidi a in (CBDV) [23].
2.1. Endocannabinoid Sys em
The endocannabinoid sys em (ECS) is a phylogene ically old modula o y sys em, ound in bo h
e eb a e and in e eb a e species [
24
–
26
]. The ECS encompasses eCB molecules, amongs which
he wo bes known and cha ac e ized a e N-a achidonoyle hanolamine (anandamide, AEA) and
2-a achidonoglyce ol (2-AG), hei syn he izing and deg ading enzymes, he wo majo cannabinoid
ecep o s CB1R and CB2R, he endocannabinoid memb ane anspo e (EMT) and he CB1R
in e ac ing p o ein 1a (CRIP1a) [1].
The i s iden i ied eCB was AEA [
1
]. B ie ly a e , wo o he eCBs we e iden i ied, namely 2-AG
and 2-a achidonoyl glyce yl e he , commonly known as noladin. eCBs a e equi alen ega ding he
Molecules 2019,24, 1350 3 o 59
p esence o a polyunsa u a ed a y acid moie y (such as he a achidonic acid) and a pola head g oup,
composed by e hanolamine o glyce ol (Figu e 1) [27–30].
Figu e 1. Endocannabinoid signaling. (A) Endocannabinoid Re og ade Signaling and Me abolism.
Molecules 2019,24, 1350 4 o 59
2-a achidonoglyce ol (2-AG) is syn hesized by wo di e en me abolic pa hways: ia he clea age
o diacylglyce ol by diacylglyce ol lipase (DAGL), whe e diacylglyce ol is eleased om memb ane
phospholipids by phospholipase C (PLC) o ia he ac ion o phospholipase A1 (PLA1), eleasing an sn-1
lysophospholipid om memb ane phospholipids, which is clea ed by lyso-PLC in o de o gene a e
2-AG. On he o he hand, a calcium-dependen ans-acylase (NAT) ac s on glyce ophospholipids
and phospha idyle hanolamine, esul ing in N-a achidonoyl-phospha idyl e hanolamine (NA PE),
which is hen clea ed by a calcium-dependen NAPE (N-acyl-phospha idyle hanolamine)-speci ic
phospholipase D (NAPE-PLD), eleasing N-a achidonoyle hanolamine (anandamide, AEA) om
memb ane lipids. While hyd olysis o AEA occu s pos synap ically, ia a y acid amide hyd olase
(FAAH) in o a achidonic acid and e hanolamine, 2-AG is hyd olyzed by monoacylglyce ol lipase
(MAGL) in o a achidonic acid and glyce ol p esynap ically. AEA and 2-AG a e usually syn hesized
pos synap ically and a e eleased “on demand” o he synap ic cle , whe e hey modula e p esynap ic
glu ama e gic o GABAe gic signaling by binding o CB1R o CB2R. (
B
) Non- e og ade Signaling.
AEA and 2-AG signal au oc inally and non- e og adely, he pos synap ic neu on, modula ing synap ic
ansmission. (
C
) Neu on-glia Signaling. Endocannabinoids p oduced by neu ons can bind o he
cannabinoid ecep o s exp essed in as ocy es and mic oglia. This neu on-glia signaling is able o
modula e se e al esponses. (
D
) eCB s uc u es. 2-AG and AEA ha e simila molecula s uc u es.
They a e bo h pola es e lipids o med by he bond o he omega-6 a y acid a achidonic acid wi h
ei he glyce ol ( o o m 2-AG) o e hanolamine ( o o m AEA).
AEA is known o ac as a pa ial agonis o CB1Rs and CB2Rs, while 2-AG as a
ull agonis o bo h ecep o s. AEA is syn hesized ia he ac ion o a calcium-dependen
ans-acylase (NAT) on phosphoglyce ides and phospha idyle hanolamine. The esul ing
N-a achidonoyl-phospha idyl e hanolamine (NA PE) is hen clea ed by a calcium-dependen NAPE
(N-acyl-phospha idyle hanolamine)-speci ic phospholipase D (NAPE-PLD), eleasing he AEA om
memb ane lipids. This eCB is hyd olyzed in o a achidonic acid and e hanolamine by a y acid amide
hyd olase (FAAH) [
31
]. 2-AG, on he o he hand, can be syn hesized by wo di e en me abolic
pa hways: ia he clea age o diacylglyce ol by diacylglyce ol lipase (DAGL), whe e diacylglyce ol is
eleased om memb ane phospholipids by phospholipase C (PLC) o ia he ac ion o phospholipase
A1 (PLA1), eleasing an sn-1 lysophospholipid om memb ane phospholipids, which is clea ed by
lyso-PLC in o de o gene a e 2-AG. This eCB is hyd olyzed by monoacylglyce ol lipase (MAGL) in o
a achidonic acid and glyce ol (Figu e 1A) [
31
]. These molecules a e no s o ed in esicles bu a he
a e syn he ized and eleased “on demand,” wi h AEA being less abundan han 2-AG [1,32].
eCBs display a b oad spec um o physiologic ele an oles, pa icula ly in he CNS and
pe iphe al ne ous sys em (PNS) [
30
,
33
]. These oles a e mainly media ed h ough he ac i a ion
o CB1Rs and CB2Rs, bo h being G p o ein-coupled se en ansmemb ane domain ecep o s
(GPCR) [
33
]. A common ea u e usually associa ed wi h CB1R and CB2R ac i a ion is he modula ion
o ei he spon aneous o e oked elease o chemical messenge s, al hough his e ec is much be e
cha ac e ized o CB1Rs [
34
]. eCBs a e p oduced and eleased om pos synap ic neu ons ei he
phasically (in an ac i i y-dependen manne ), o onically (unde basal condi ions). The eleased eCBs
hen ac e og adely by ac i a ing p esynap ic ecep o s (Figu e 1A) [
33
,
35
]. Hence, egula ion o
neu o ansmi e elease cons i u es a majo physiological ole o he ECS [
30
]. Indeed, eCBs a e
in ol ed in impo an o ms o sho and long- e m plas ici y, by supp essing neu o ansmi e elease
ansien ly (sho - e m dep ession, STD) o pe sis en ly (long- e m dep ession, LTD), mainly h ough
he ac i a ion o p esynap ic CB1Rs [
33
]. Impo an ly, eCBs can con ol bo h inhibi o y synap ic
ansmission (a p ocess designa ed as depola iza ion-induced supp ession o inhibi ion, DSI) and
exci a o y synap ic ansmission ( he depola iza ion-induced supp ession o exci a ion, DSE) [36,37].
A ailable e idence also sugges s ha eCB signaling can occu in a non- e og ade mode, h ough
au oc ine signaling. Speci ically, eCBs can modula e synap ic ansmission h ough di ec ac i a ion o
ansien ecep o po en ial anilloid ecep o ype 1 (TRPV1R), in which AEA is known o ac as a ull
agonis , o ia pos synap ically loca ed CB1Rs (Figu e 1B) [38,39].
Molecules 2019,24, 1350 5 o 59
The abundancy o CB1Rs in he b ain s ongly suppo s ha his ecep o is esponsible o he
majo i y o he psychoac i e e ec s o exogenous cannabinoids and o he physiological ac ions o
eCBs [
25
,
33
]. This is u he suppo ed by he ac ha selec i e CB1R an agonis s e ec i ely abolish
he psychoac i e e ec s o hese d ugs [
40
]. As e iewed by Solymosi and Kö al i (2017), he CB1R is
abundan ly p esen in he CNS, wi h highe densi ies ound in he subs an ia nig a pa s e icula a,
globus pallidus, en opeduncula nucleus, inne g anule cell laye (GCL) o he ol ac o y bulb, laye s
I-III, Va and VI o he ce eb al co ex, hippocampus (pa icula ly in he molecula laye and Co nu
Ammonis 3 (CA3) egion) and do sola e al s ia um; mode a e le els o CB1Rs can be ound in he
hypo halamus, en al s ia um/nucleus accumbens, sep um and amygdala [1,41,42].
CB1R ac i a ion has been linked o neu op o ec ion by con olling excessi e exci a o y
ansmission and calcium elease, hus p o ec ing synapses om exci o oxi y [
43
]. Al hough being
classically iewed as a G
i/o
-coupled ecep o , hence ha ing mainly inhibi o y ac ions, CB1R coupling
o G p o eins is mu able [
30
,
33
,
44
]. Indeed, CB1R is now belie ed o ha e ew “in insic” signaling
p ope ies, and he ac ions media ed by i s ac i a ion a e la gely dependen on cell ype, loca ion,
unc ional s a e and empo al cons ains ( o a de ailed e iew see [
44
]). All hese nuances can
d as ically modi y he e ec s o endo-, exo- and syn he ic cannabinoids.
Con a y o ini ial belie ha CB2Rs we e exclusi ely p esen in he pe iphe y, pa icula ly in he
immune sys em, such as in he spleen, leukocy es and onsils, hese ecep o s we e la e iden i ied
in mic oglial cells [
33
,
45
–
48
]. New and mo e ad anced echnological app oaches ha e allowed he
iden i ica ion o CB2Rs in as ocy es and, o a la ge deg ee, in neu ons (Figu e 1C) [
49
–
51
]. In he
CNS, hey we e i s iden i ied in b ains em neu ons and la e in inhibi o y and exci a o y neu ons in
he hippocampus [
52
,
53
]. Nowadays, CB2Rs a e known o be exp essed in he p esynap ic e minals o
gaminobu y ic acid-con aining (GABAe gic) in e neu ons in he hippocampus and medial en o hinal
co ex, and in co ical and hippocampal as ocy es, whe e CB2R ac i a ion leads o highe glucose
up ake [
54
,
55
]. CB2R le els can be inc eased in neu ons and as ocy es ollowing speci ic insul s
(such as neu oin lamma ion) and also in ce ain disease s a es [
56
–
58
]. Addi ionally, conside ing he
lack o psychoac i e e ec s ollowing CB2R modula ion, his ecep o is becoming popula as a e y
p omising he apeu ic a ge [46].
When aking in o accoun he psychoac i e and he apeu ic p ope ies o cannabinoids, i is
impo an o conside ha he phy ocannabinoids exis en in he cannabis plan , and in o he plan s,
a ec b ain ac i i y by coupling o o he ecep o s beyond he classic CB1Rs and CB2Rs [
1
,
23
]. Being so,
se o onin 5HT1-3A ecep o s (5HT1AR, 5HT2AR, 5HT3AR), G p o ein-coupled ecep o s 18 and 55
(GPR18, GPR55), ansien ecep o po en ial (TRP) amily, glycine ecep o s and he pe oxisome
p oli e a o -ac i a ed ecep o (PPAR) assume a pa icula impo ance when conside ing he possible
he apeu ic applica ions o cannabinoids [
1
,
23
]. Ana omical and unc ional co-localiza ion s udies
ha e shown ha hese ecep o s a e exp essed in he same egions as CB1Rs and CB2Rs in he CNS
and PNS [59–62].
2.2. Cannabinoid Pha macology and Ac ions
∆9
-THC and CBD a e he wo bes known and cha ac e ized phy ocannabinoids. The ca alep ic
e ec o
∆9
-THC was he i s psychoac i e e ec desc ibed o a cannabinoid [
63
]. This e ec is used as
a s anda d o cannabinoid psychoac i i y, wi h which i has been shown o be s ongly co ela ed [
64
].
∆9
-THC is known o ac as a pa ial agonis o CB1Rs and CB2Rs, p esen ing a mixed
agonis -an agonis p o ile depending on he cell ype, concen a ion, ecep o exp ession and p esence
o o he endo- and exo-cannabinoids ac ing as ull agonis s [
23
,
65
,
66
]. As e iewed by Solymosi and
Kö al i (2017),
∆9
-THC can ha e di e en coupling p o iles [
1
]. In ac , some epo s show ha
∆9
-THC
can be mo e po en on he CB2Rs and, pa adoxically, a highe concen a ions i may e en ac as an
an agonis o CB1Rs [
65
,
67
,
68
].
∆9
-THC is conside ed a “classic cannabinoid” because i passes he
mouse e ad bioassay h ough he ac i a ion o CB1Rs, by elici ing he cannabinoid-induced e ad
(hypo he mia, hypolocomo ion, ca alepsy and analgesia) [
64
,
69
]. As ho oughly e iewed by Solymosi

Molecules 2019,24, 1350 6 o 59
and Kö al i (2017), besides i s ac ions on CB1Rs and CB2Rs, ∆9-THC binds o se e al o he ecep o s
such as GPR55, as well as se o onin, opioid, glycine and PPAR
γ
ecep o s, which may accoun o some
o he e ec s desc ibed o his phy ocannabinoid [
1
,
23
]. Howe e ,
∆9
-THC has been shown o ha e
no e ec on he TRPV1R, al hough i ac s on o he TRPV channels ( o de ailed e iews see [1,23]).
CBD is a non-psychoac i e cannabinoid, he e o e, has high medicinal alue, being widely
s udied. This cannabinoid has been shown o ac as an an i-in lamma o y, an ioxidan , an i-epilep ic,
an i heuma ic, anxioly ic and analgesic d ug [
1
,
23
]. CDB was also shown o educe conges ion and
nausea and o be neu op o ec i e [
1
,
23
]. Fu he mo e, CBD posi i ely modi ies he e ec s o
∆9
-THC
by educing i s psychoac i e e ec s and by inc easing i s clinical e icacy and he du a ion o i s
bene icial e ec s [
1
,
22
]. CBD was ea ly cha ac e ized as absen o ca alep ic e ec s, which p omp ed
he now well accep ed e idence ha CBD is de oid o psychoac i e e ec s [63,64].
As e iewed by Solymosi and Kö al i (2017), CBD has low a ini y o CB1Rs and CB2Rs, exhibi ing
no agonis ac i i y [
1
,
67
,
70
]. On he con a y,
in i o
s udies ha e shown ha CBD has su p isingly
high po ency as an an agonis o bo h CB1Rs and CB2Rs [
71
]. Recen ly, howe e , i is being p oposed
ha CBD may ac ually ac as a nega i e allos e ic modula o o CB1Rs [
72
]. Fu he mo e, i inhibi s
he cellula eup ake o AEA, di ec ly a ec ing eCB one [
23
]. I also ac s as an agonis o GPR55 and
as an an agonis o GPR18 [
68
,
73
,
74
]. In a ecen wo k, he an i-in lamma o y and immunosupp essi e
e ec s o CBD we e p oposed o be linked wi h i s abili y o ac i a e adenosine ype 1 ecep o s [
75
].
CBD e ec s on TRPV, glycine, GABAAand PPARγ ecep o s we e desc ibed in de ail in [23].
eCBs, phy ocannabinoids such as
∆9
-THC and CBD, as well as o he syn he ic cannabinoids, we e
shown o modula e emb yonic and pos na al neu ogenesis. In he nex sec ions o his e iew, we will
u he explo e he ole o he ECS in NSC modula ion and i s implica ions o pa hophysiology.
3. Neu ogenesis
3.1. Neu ode elopmen al Neu ogenesis
Du ing emb yonic de elopmen , neu ogenesis can be dis inguished in wo di e en s ages
ha , al hough ha ing di e en cellula and molecula mechanisms, occu simul aneously. These a e
neu ula ion and emb yonic neu ogenesis.
3.1.1. Neu ula ion
A ising om he ec ode m, one o he h ee p ima y ge m laye s, he CNS begins de eloping
when he neu al pla e olds in o he neu al ube, h ough a p ocess called neu ula ion, gi ing o igin o
he b ain in he os al egion and he spinal co d in he caudal egion [
76
]. Du ing his s age he e is an
inc ease in he numbe o neu oec ode m-de i ed p oli e a ing cells, expanding he neu al epi helium
a di e en a es in o de o o m mo e specialized egions o he ma u e CNS [
77
]. These hen become
he o eb ain, he midb ain and he hindb ain. Simul aneously, se e al ac o s a e eleased om
he no ocho d and he somi es a ound he neu al ube, es ablishing a do so en al pola i y [
78
].
This pola i y is u he ein o ced by he o ma ion o he an e io -pos e io axis h ough he Wn
signalling g adien (Figu e 2A) [79].
Molecules 2019,24, 1350 7 o 59
Figu e 2.
Neu ogenesis. (
A
) Neu ula ion. Schema ic ep esen a ion o he neu ula ion p ocess.
Neu oec ode m de i ed cells p oli e a e a di e en a es along he apicobasal pola i y. (
B
) Emb yonic
Neu ogenesis. Du ing emb yonic de elopmen he cen al ne ous sys em de elops in an inside-ou
ashion. Neu oepi helial s em cells, ia asymme ical di isions, di e en ia e in o adial glial cells
(RGCs), es ablishing he Ven icula Zone nea he apical su ace. Nea he pial su ace, Cajal- Re zius
(CRCs) cells will make he ma ginal zone du ing emb yogenesis and he co ical laye I pos na ally.
The o he co ical laye s a e o med in sequen ial wa es du ing neu ogenesis. La e in de elopmen ,
Molecules 2019,24, 1350 8 o 59
neu al p ogeni o s en e a gliogenic mode, gene a ing as ocy es and oligodend ocy es. Neu oepi helial,
adial glial and in e media e p ogeni o cells a e capable o symme ic and asymme ic di isions.
(
C
) Pos na al Neu ogenesis. In he adul b ain, neu al s em cells can be ound in wo neu ogenic niches,
he Sub en icula Zone (SVZ) and in he Subg anula cell laye o he Den a e Gy us (DG). In oden s
(
C1
), a e di e en ia ing in he SVZ, imma u e neu ons mig a e along he os al mig a o y s eam
(RMS) o he ol ac o y bulb (OB) whe e hey will ma u e mainly in o GABAe gic in e neu ons. On he
o he hand, in humans (C2), imma u e neu ons a e hough o mig a e along he RMS o he s ia um
(STR). In oden s and humans, di e en ia ing neu ons om he DG ma u e by making unc ional
connec ions wi h py amidal CA3 hippocampal neu ons.
3.1.2. Emb yonic Neu ogenesis
Neu oepi helial p ogeni o cells (NECs) can be ound lining inside he neu al ube, which will
de elop in o he en icles [
80
]. They o m a pseudos a i ied epi helium, as hei nuclei mig a e
wi h he cell-cycle s age (in e kine ic nuclea mig a ion), being nea he apical side du ing mi osis
and mo e basally du ing he S phase [
81
]. Like o he s em cells, NECs di ide in ei he a symme ic
p oli e a i e manne , in which bo h daugh e cells emain mi o ic, o in a di e en ia i e manne , in
which a leas one daugh e cell exi s he cell cycle and di e en ia es in o a mo e specialized cell [
82
].
This ounda ional p ocess o ms se e al laye s su ounding he lumen o he de eloping ne ous
sys em, he inne -mos apical laye , whe e he p ogeni o cells eside, being he en icula zone
(VZ). Radial glial cells (RGCs) a e he ea lies ype o cells o be dis inguishable wi hin he neu al
epi helium. The cell bodies o hese cells can be ound in he VZ and hei long p ocesses ex end
ou wa ds, o he pial su ace [
83
]. Ou e RGCs and in e media e p ogeni o s will hen es ablish he
sub en icula zone (SVZ), which becomes one o he adul neu ogenic niches. RGCs will o igina e
ansi ampli ying cells o inc ease neu onal p oduc ion [
83
,
84
]. NECs exi he cell cycle nea he
en icula su ace and in ade he p epla e (PP—a p imo dial pla e abo e he VZ). Mig a ing neu ons
mo e pas he subpla e, displacing his laye away om he Cajal-Re zius cells (CRCs), which emain
adjacen o he pial su ace o he de eloping b ain in a cell-spa se a ea known as he ma ginal zone [
85
].
Dis inc p ojec ion neu on sub ypes a e bo n in sequen ial wa es o e he cou se o neu ogenesis [
86
].
As new co ical pla e neu ons a i e o he RGCs, hey mig a e pas he olde subpla e and co ical
pla e neu ons be o e inse ing benea h CRCs [
87
]. This inside-ou a angemen o p ojec ion neu ons
makes he oldes neu ons (co ical laye VI) closes and he younges neu ons (co ical laye II/III)
a hes om hei bi hplace nea he en icle (Figu e 2B). This co ical expansion, despi e being
conse ed wi hin all mammalian species, is di e en whe he o ganisms ha e a smoo h (lissencephalic,
e.g., mouse, a ) o highly con olu ed (gy encephalic, e.g., e e , human) neoco ex [
88
,
89
]. One key
di e ence is associa ed wi h he size o he neoco ex, which can be be e co ela ed wi h i s su ace
a ea han wi h i s hickness, which only a ies sligh ly ac oss species [
90
]. B ain con olu ions appea ed
as an e olu iona y solu ion o he p oblem o inc easing co ical su ace a ea (e.g., neu on numbe s)
wi hou p ohibi i ely inc easing he size o he skull [
91
]. Ano he s iking in e species di e ence
is ela ed o he expansion o he basal p ogeni o s [
92
]. In gy encephalic species, he SVZ can be
u he dissec ed in wo dis inc ge minal zones: he inne SVZ, which la gely esembles he SVZ
o lissencephalic oden s, and he ou e SVZ, which is absen in mos lissencephalic species [
92
].
This subdi ision o he SVZ has a emendous impac on he numbe o basal p ogeni o s con ained
in each laye . Indeed, du ing peak s ages o emb yonic neu ogenesis, he ou e SVZ ha bo s up o
ou imes as many p ogeni o s as he VZ and inne SVZ combined [
93
]. Howe e , his does no
co ela e wi h a highe numbe o neu ons in he adul b ain. In ac , in la e de elopmen al s ages, a e
emb yonic neu ogenesis is comple e, neu al p ogeni o s ansi ion in o a gliogenic mode, gene a ing
as ocy es and oligodend ocy es [
94
,
95
]. CRCs will mig a e in o he neoco ical laye I o he co ex
om non-co ical loca ions, whe eas p ojec ion neu ons bo n in he neoco ical VZ and SVZ, mig a e
along adial p ocesses o each hei inal lamina des ina ions in he co ex [
96
]. The p esence o
NSCs in mos CNS egions dec eases d ama ically a e emb yonic de elopmen bu , in many species,
emains h oughou li e in localized neu ogenic niches [97–100].
Molecules 2019,24, 1350 9 o 59
3.2. Adul Neu ogenesis
Adul NSCs can be mos ly ound in wo neu ogenic niches, he SVZ and he subg anula zone
(SGZ) o he hippocampal den a e gy us (DG) (Figu e 2C) [101]. The exis ence o sel - enewing adul
NSCs in he b ain led o he hypo hesis ha NSCs a e i-po en , ha ing he capaci y o gene a e
neu ons, as ocy es, and oligodend ocy es. Howe e , he pionee ing
in i o
s udies in he adul
hippocampus by E iksson and colleagues ha e only ound he gene a ion o neu ons and as ocy es,
bu no oligodend ocy es [
102
]. On he o he hand,
in i o
s udies ocusing on he adul SVZ sugges
ha NSCs can gi e ise o he h ee neu al cell ypes, bu whe he neu ons and glia a ise om dis inc
s em cell lineages in i o is s ill unknown [103].
Adul NSCs a e mos ly quiescen
in i o
due o he speci ic cellula and molecula cha ac e is ics
o he niches whe e hey eside, allowing hem o wi hs and me abolic s ess and o p ese e genome
in eg i y o e long pe iods o ime [
104
,
105
]. The balance be ween he cy oa chi ec u e o he niches
and he ac o s ha egula e quiescence and ac i a ion o NSCs is so delica e ha i has been p oposed
ha umo igenic o b ain umo s em cells may a ise om an imbalance o hose ac o s [
106
]. In ac ,
bo h NSCs and umo igenic cells sha e many o he molecula pa hways ha egula e p oli e a ion,
such as sonic hedgehog (shh) o Wn -signalling [106].
Despi e ha ing been shown o exis in se e al mammals since he 1960s (e.g., mice, a s, ca s,
song bi ds, eesh ews, ma mose s, macaques), in humans, adul neu ogenesis has spa ked an in ense
deba e ega ding i s exis ence [
107
–
112
]. Repo s o human neu ogenesis a e mos ly based on he
analysis o neu ogenic ma ke s, namely doubleco in (DCX) and polysialic acid neu al cell adhesion
molecule (PSA-NCAM) on pos -mo em b ain samples [
102
,
113
–
115
]. I has been sugges ed ha he
di e ences ound in s udies whe e human adul neu ogenesis is ei he p o ed o disp o ed could
be due o se e al ac o s a ound he ime o dea h, namely s ess ho mones, p o ein in eg i y and
he gene al heal h s a e o subjec s; o e en he pos -mo em delay be ween sample collec ion and
p epa a ion [
116
,
117
]. In ac , i has been shown in animal s udies ha he DCX signal becomes weak
wi hin a ew hou s o pos -mo em delay, he e o e ime is a c ucial ac o on neu ogenesis s udies,
impac ing he o e all analysis o da a [
118
]. A ecen s udy by So ells and colleagues (2018) showed
ha adul neu ogenesis d ops o unde ec able le els wi h aging. This s udy was conduc ed wi h
samples om pa ien s wi h epilepsy, whe e no mal hippocampal ci cui y and neu ogenesis is known
o be dis up ed and had a pos -mo em delay o a ound 48 h be ween collec ion and ixa ion [
113
].
On he o he hand, in Bold ini e al. (2018) and mo e ecen ly in Mo eno-Jiménez e al. (2019) s udies,
epo ed li elong neu ogenesis in humans. In hese s udies he pos -mo em delay was no longe han
26 h and samples we e collec ed om bo h con ol and pa hological subjec s [
114
,
115
]. Su p isingly,
in Mo eno-Jiménez e al. (2019) s udy, samples om pa ien s wi h Alzheime ’s disease (AD) also ha e
imma u e p ogeni o cells, i.e., DCX posi i e cells, al hough he numbe and ma u a ion o hese cells
p og essi ely declined as AD ad anced, again ein o cing he idea ha issue handling is essen ial o
he p ese a ion and de ec ion o neu ogenic ma ke s [115].
3.2.1. Sub en icula Zone
Ependymal cells a e o ganized in o ose e shaped s uc u es bo de ing he SVZ which is lining
he la e al wall o he la e al en icles. The e a e h ee cell ypes ha mainly compose he SVZ niche:
B cells, C cells and A cells. B cells (o adial glia-like NSCs) ex end adial p ocesses o con ac wi h
blood essels and a single cilium h ough he ependymal ose es o con ac he ce eb ospinal luid
in he en icula space [
119
]. These p ocesses allow he de ec ion o bo h in insic (e.g., shh, Wn
o No ch-signaling) and ex insic ac o s (e.g., neu o ansmi e s, ho mones o g ow h ac o s) ha
will signal o ei he p oli e a ion, di e en ia ion, o bo h [
120
]. B cells can di ide and di e en ia e
in o C cells (o ansi ampli ying cells), which hen gene a e A cells (o neu oblas s) [
121
]. In oden s,
neu oblas s mig a e down he os al mig a o y s eam (RMS) o he ol ac o y bulb whe e hey
di e en ia e mainly in o GABAe gic in e neu ons and a e in eg a ed ei he in he GCL o in he
pe iglome ula laye . Thus, SVZ neu ogenesis plays an impo an ole in he neu oplas ici y and
Molecules 2019,24, 1350 16 o 59
b ain-de i ed neu osphe es, and ha in e leukin 1 (IL-1) signaling pa hway was in ol ed in his
p ocess, emphasizing he neu oimmune in e ac ions o cannabinoid signaling [241].
O e all, mos e idence shows ha gene ic abla ion o cannabinoid ecep o s o ea men wi h
CB1R and CB2R selec i e an agonis s leads o a dec ease in NSC p oli e a ion in he hippocampus
and SVZ [
175
,
213
,
217
]. By con as , ei he di ec ac i a ion o cannabinoid ecep o s using syn he ic
agonis s and/o an indi ec app oach aiming a inc easing eCBs, by inhibi ing hei deg ading enzymes,
s imula es he o ma ion and ma u a ion o new neu ons in bo h adul niches [213,242,243].
The complexi y/ a iabili y o hese indings also illus a es ha s udy design, animal species,
s ain, gende and/o compound selec i i y and dosage a e e y impo an when s udying he e ec s
o cannabinoids in NSC egula ion. Mo eo e , da a dispa i y o many s udies in ol ing adul NSCs
may in pa be explained by he a ying p ope ies o each NSC popula ion and he he e ogenei y
wi hin each NSC pool, which sugges s ha eCB signals, ac ing in a pa icula spa ial and empo al
manne , could di e en ially a ec he p oli e a i e capaci y o NSCs, limi ing he lineage speci ica ion
o succeeding p ogenies. In ac , he e a e di e gences be ween he wo niche mic oen i onmen s
ega ding he molecules ha egula e mo phogenesis, a es o di ision, sel - enewal and su i al
which may accoun o he obse ed di e ences [244,245].
5. Role o Cannabinoids in Neu ogenesis and Pa hophysiology
Neu ological and men al diso de s comp ise a b oad ange o disabling condi ions wi h di e en
pheno ypic ou pu s. Some symp oms o hese diso de s may a ise om ea ly impai men in neu al
de elopmen o abe an adul neu ogenesis [
246
]. In ac , al e a ions in he mechanisms behind NSC
egula ion in he emb yonic and adul b ain ha e been epo ed in bo h pa ien s and animal models o
AD, Pa kinson’s disease (PD), MS, epilepsy and mood diso de s [247–251].
Despi e he ex ensi e e idence sugges ing ha bo h exogenous and endogenous cannabinoids
egula e NSC p oli e a ion, which in u n may be a ec ed by disease loading, he link be ween NSCs,
cannabinoids and b ain diso de s emains o be es ablished. This unclea ision may a ise om he
poo / a ied design o p e-clinical s udies, he lack o pos -mo em analyses o b ains om pa ien s wi h
neu ological diso de s as well as he lack o clinical s udies in ol ing cannabinoid usage. Howe e ,
se e al da a sugges ha manipula ion o cannabinoid signaling p omo es a ine- uned egula ion o
NSCs, which is esul an om hei an i-in lamma o y and an ioxidan p ope ies. The e o e, eCBs may
ha e an impac in delaying, p e en ing o es o ing some neu al de ici s in animal models ha
mimic some ea u es o neu odegene a i e and psychia ic diso de s, he e o e, cons i u ing po en ial
he apeu ic a ge s o neu o egene a ion.
5.1. Cannabinoids and Neu op o ec ion
B ain damage and neu odegene a ion a e leading causes o long- e m disabili y, disease bu den
and mo ali y wo ldwide [
252
]. They a e cha ac e ized by he p og essi e loss o speci ic neu onal
subpopula ions in he CNS, wi h di e en clinical ea u es being exhibi ed and can esul om he
na u al p ocess o b ain aging o b ain inju y/ auma. A ailable ea men s usually ac on ansien
symp oma ic elie , being poo ly ac i e a igh ing he cellula e en s occu ing as b ain damage
ad ances [
253
]. The e o e, i is essen ial o seek o molecules wi h disease-modi ying ac i i y ha
ake in o conside a ion he mechanisms ha unde lie disease p og ession and enable he epai o
neu onal loss.
The neu op o ec i e po en ial o ECS- a ge ing compounds (e.g., cannabinoid agonis s o
an agonis s, inhibi o s o eCB deg ada ion o biosyn hesis o o he modula o s) has been ex ensi ely
in es iga ed o e he las 20 yea s [
253
]. This neu op o ec i e na u e o cannabinoids a ises no only
om hei pleio opic p o ile, i.e., he capaci y o in e ac wi h neu omodula o y sys ems no di ec ly
ela ed wi h he eCB signaling, bu also om he p esence o hese a ge s in key cellula componen s
o he CNS (i.e., neu ons, as ocy es, mic oglia, oligodend ocy es and neu al p ogeni o cells) and
b ain s uc u es like he blood–b ain ba ie [
58
]. These ea u es hen ansla e in o an abili y o es o e

Molecules 2019,24, 1350 17 o 59
he CNS o a physiological homeos a ic s a e a e an acu e o ch onic pe u ba ion, by igh ing an
a ay o cellula p ocesses caused by b ain insul s o damage, like exci o oxici y, inc eased s a e o
neu oin lamma ion, oxida i e s ess and p o ein agg ega ion, as well as o he p ocesses ha in e e e
wi h neu onal homeos asis and in eg i y [
253
]. Gi en he ela ionship be ween all hese pa hological
cellula hallma ks, he p o ec ion o CNS componen s mus ac on all o mos o hese a ge s in a
mul i ace ed manne . The e o e, cannabinoids a e aluable candida es o his s a egy.
Excessi e elease o glu ama e gene a es accumula ion o oxic concen a ions o in acellula
calcium and oxygen ee adicals, esul ing in exci o oxici y, a p ocess common o many b ain
diso de s which o en leads o neu onal dea h [
254
]. A numbe o obse a ions indica e he abili y
o cannabinoids o con ol glu ama e elease h ough he ac i a ion o CB1Rs and ha e e ealed a
c ucial ole o his ecep o in exci o oxici y con ol, BDNF being a key media o o his p ocess [
43
,
255
].
O he s ha e also demons a ed ha cannabinoid-media ed neu op o ec ion agains exci o oxici y elies
on CB1R and CB2R modula ion in glial cells [
256
]. Mo eo e , inhibi ion o eCB up ake wi h UCM707
was shown o ha e a p o ec i e ole agains AMPA-induced exci o oxici y h ough ac i a ion o CB1Rs,
CB2Rs and PPARγs [257].
While he mechanisms o neu op o ec ion aimed a egula ing glu ama e homeos asis a e
mainly due o CB1R ac ions, he an i-in lamma o y e ec s o cannabinoid-media ed p o ec ion a e
mos ly a ibu ed o he modula ion o CB2Rs. Hence, he in ol emen o he ECS, pa icula ly o
CB2Rs, in educing local o sys emic in lamma o y e en s is a c ucial pa o cannabinoid-media ed
neu op o ec ion. Neu oin lamma ion is he p ocess by which he elease o cy o oxic agen s and cell
dea h occu s a e acu e o ch onic CNS damage [
258
]. The egula ion by cannabinoids o mechanisms
like modula ion o immune esponses and he elease o in lamma o y media o s was ex ensi ely
e iewed in [
259
]. Fo ins ance, mouse mic oglial cell cul u es ea ed wi h CB2R selec i e agonis
JWH015 showed a educ ion in in e e on-
γ
(IFN-
γ
)-induced up egula ion o CD40 exp ession, which
lead o a dec ease in he p oduc ion o p oin lamma o y cy okines and an enhancemen o amyloid-
β
(A
β
) phagocy osis [
260
]. Mo eo e , adminis a ion o CBD and WIN 55,212-2 was shown o educe
he le els o p oin lamma o y cy okine IL-6 de i ed om A
β
exposu e [
261
]. Fu he s udies ha e
epo ed ha o al adminis a ion o JWH-133, a po en CB2R agonis , dec eased mic oglial ac i a ion,
p oin lamma o y ac o s COX-2 and umo nec osis ac o
α
(TNF-
α
) mRNA exp ession and he
co ical le els o A
β
in a ansgenic mouse model o AD [
262
]. In he con ex o aging, which is closely
ela ed wi h an inc ease in neu oin lamma ion, aged a s adminis e ed wi h WIN 55,212-2 showed a
educed numbe o ac i a ed mic oglia in he hippocampus and DG. Fu he mo e, he same ea men
was ound o dec ease he mRNA le els o he IL-6, as well as he p o ein le els o he in lamma o y
ac o s TNF-αand IL-1β[263].
In like manne , cannabinoid ecep o ligands a e o en epo ed as ha ing an ioxidan p ope ies
because hey a e able o igh oxida i e s ess and educe eac i e oxygen species (ROS) load,
p ocesses in ima ely associa ed wi h exci o oxici y and neu oin lamma ion. Fo example,
∆9
-THC
exposu e was shown o escue he pha macologically-induced inhibi ion o mi ochond ial unc ion,
ubiqui in p o easome and p oduc ion o ee adicals in a human neu oblas oma cell line [
264
].
Mo eo e , ea men wi h CBD p omo ed po en an ioxidan ac ions in bo h
in i o
and
in i o
s udies
by educing ROS bu den [265,266].
In addi ion o he bene i s esul ing om di ec ac i a ion o he ECS, he abili y o eCBs o in e ac
wi h o he molecules/sys ems can also p o ide neu op o ec i e ac ions. In ac , cannabinoid-media ed
neu op o ec i e e ec s also esul om in e ac ions wi h ansc ip ion ac o s, neu o ophic ac o s,
ecep o s o he PPAR amily o wi h elemen s o o he ansmission sys ems, like he se o onin 5-HT1A
ecep o s o adenosine A2A ecep o s [267–272].
Impo an ly, he ECS has been shown o be in ol ed in he neu op o ec ion o NSCs and hei
esul ing p ogeny. In ac , CB1Rs we e shown o be in ol ed in he exci o oxici y-induced neu al
p ogeni o cell p oli e a ion and neu onal di e en ia ion [
273
]. Mo eo e , ac i a ion o CB2Rs was
shown o inc ease he su i al o NSCs and p ogeni o cells, as well as o escue impai ed hippocampal
Molecules 2019,24, 1350 18 o 59
neu ogenesis caused by ch onic insul by HIV-1 neu o oxic p o ein gp120 [
226
]. Mo e ecen ly,
ac i a ion o GPR55 has demons a ed a neu o-immune egula o y ole o human and mu ine NSCs by
p o ec ing hem agains ch onic in lamma ion
in i o
(wi h IL-1
β
ea men ) and
in i o
(wi h ch onic
LPS adminis a ion) [274].
Despi e he neu op o ec i e ac ions associa ed wi h he ECS modula ion, cannabinoid-induced
neu o oxic e ec s ha e also been epo ed [
252
]. This inconsis ency may be due o nume ous ac o s,
such as he se e i y and iming o he pa hologically-induced insul and, he kind o pha macological
in e en ion implemen ed. The dosage and iming o adminis a ion o cannabinoids a e also o
g ea impo ance, gi en ha high exposu e usually induces neu onal cell dea h [
275
]. Mo eo e ,
di e en cannabinoids ha e di e en mechanisms o ac ion depending on he ype o ecep o s hey
modula e and he co esponding signaling pa hways.
In he nex sec ions, illus a i e examples o ECS sys em modula ion in disease con ex will be
desc ibed in mo e de ail (Supplemen a y Table S1).
5.2. Cannabinoids and B ain Diso de s
5.2.1. Alzheime ’s Disease
La e-onse AD (
≥
65 yea s-old) is esponsible o abou 70% o all cases o demen ia [
276
].
The disease is cha ac e ized by a numbe o A
β
oligome iza ion and agg ega ion-induced neu o oxic
mechanisms, including au hype phospho yla ion, neu oin lamma ion wi h eac i e gliosis (as o and
mic ogliosis), exci o oxici y and oxida i e damage [
277
–
279
]. These changes, which p ima ily impac
on he co ex and he hippocampal o ma ion, esul in dis up ed synap ic plas ici y, loss o synap ic
unc ion, namely choline gic, and cell dea h [
277
–
279
]. Despi e being one o he mos debili a ing
neu odegene a i e diso de s, p esen a ailable ea men op ions ha e ailed o s op o e en
signi ican ly delay disease p og ession [
278
]. Due o i s b oad ange o ac ions a he PNS and CNS,
modula ion o he ECS has been ex ensi ely discussed as a po en ial mul imodal disease-modi ying
he apy o he managemen o complex mul i ac o ial condi ions such as AD ( e iewed in [
7
,
280
,
281
]).
AD pa ien s classically show a slow-p og essing cogni i e impai men , no ably a ec ing sho - and
long- e m memo y pe o mance, which a e highly dependen on hippocampal unc ion [
277
,
282
,
283
].
Howe e , clinical e idence assessing he po en ial bene i o cannabinoids on cogni i e decline is
cu en ly lacking [
284
]. None heless, a ew pa ien ials ha e ocused on he use o he THC-based
pha maceu ical o mula ion d onabinol (Ma inol
®
) o elie ing neu opsychia ic symp oms shown by
mos demen ed indi iduals, deno ing a dec ease in agi a ion, noc u nal mo o ac i i y and agg essi e
beha io s, as well as an inc ease in body weigh [285–288].
Changes in se e al componen s o he ECS ha e been desc ibed in AD pos -mo em samples and
animal models o he disease. Despi e con adic ing esul s, hese changes appea o be dependen
on he ype o cells, bu also on disease s age, and A
β
agg ega ion s a e [
7
,
289
]. In his ega d,
an ini ial inc ease o CB1Rs is p oposed o occu , ollowed by a down egula ion a la e s ages [
290
].
In e es ingly, CB2Rs a e o e exp essed in mic oglia su ounding neu i ic plaques, ye dec eased
in neu ons [
50
,
291
,
292
]. Inc eased 2-AG signaling is also obse ed a ound A
β
plaques in la e-AD,
in associa ion wi h diminished MAGL ac i i y and enhanced DAGL exp ession [
293
,
294
]. In addi ion,
augmen ed FAAH ac i i y and exp ession can be deno ed in as ocy es nea plaques, wi h subsequen
educ ion o AEA [291].
How he egene a i e capabili y o he adul b ain is modula ed in aging and AD is s ill a
ma e o deba e, wi h a iable esul s om
in i o
and
in i o
(bo h pha macological and ansgenic)
animal models and pos -mo em human samples [
295
]. Howe e , mos e idence poin s o a deple ion
o p oli e a ion, di e en ia ion and su i al o NSCs, as well as comp omised mo phology and
ma u a ion o GCs in he DG o mouse models o AD [
296
–
302
]. Mo eo e , as o he ECS, al e a ions
in AHN a e sugges ed o be dependen on disease p og ession and A
β
con o ma ion, being ini ially
Molecules 2019,24, 1350 19 o 59
ele a ed as an a emp o compensa e o neu o oxici y and cell dea h, ye ading a la e disease
s ages [303,304].
The use o di e en models o AD shows ex ensi e p omise ega ding he neu op o ec i e ole o
cannabinoids. A ele an unc ion o hese compounds in educing amyloid bu den and associa ed
neu o oxici y has been sugges ed
in i o
.
∆9
-THC is a compe i i e inhibi o o ace ylcholines e ase
(AChE) ac i i y, po en ially p e en ing AChE-induced A
β
agg ega ion [
305
]. Bo h 2-AG and AEA,
as well as CB1R/CB2R (WIN 55,212-2 and HU-210), and CB2R (JWH-133, JWH-015) agonis s,
ha e been shown o p e en A
β
-induced oxici y, namely by p omo ing mic oglia-media ed A
β
clea ance [
260
,
292
,
306
–
308
]. Simila e ec s o CBD o PPAR
γ
ac i a ion we e also obse ed,
demons a ing enhanced cell su i al, dec eased oxida i e s ess, and egula ion o A
β
p oduc ion
and clea ance [309–313].
Fu he mo e, many au ho s ha e ocused on he cannabinoid-media ed an i-in lamma o y ac ions,
mainly using ansgenic mouse models o AD o models ob ained by in ace eb al injec ions o A
β
o mice and a s. In hese models, neu oin lamma ion and eac i e gliosis a ound neu i ic plaques
was shown o be e ec i ely down- egula ed by MAGL inhibi ion, WIN 55,212-2, CB1R agonis ACEA,
CB2R agonis s MDA7 and JWH-133, CBD and THC+CBD [
218
,
261
,
262
,
292
,
314
–
320
]. Besides hese
e ec s, a ious s udies using he same compounds and AD models ha e demons a ed lea ning
and memo y imp o emen s, in asks ha signi ican ly ely on hippocampal unc ion, al hough some
au ho s epo no e ec on Aβload [261,262,292,293,314–319,321–323]. In line wi h his, ∆9-THC and
MAGL inac i a ion ha e been shown o dec ease he occu ence o neu i ic plaques in a ansgenic
mouse model ca ying i e mu a ions ela ed o amilial AD (5xFAD) [324,325].
I is s ill unclea whe he cannabinoids migh ha e a posi i e impac on AD pa hology,
pa ly h ough egula ion o AHN, ye a ew common pa hways may be men ioned. Some o he
a o emen ioned an i-in lamma o y and neu op o ec i e ac ions o cannabinoids ha e been linked o
he inhibi ion o glycogen syn hase kinase 3
β
(GSK-3
β
) o e ac i a ion, which is known o p omo e au
hype phospho yla ion and A
β
p oduc ion, and is a nega i e egula o o AHN [
218
,
262
,
319
,
320
,
326
–
329
].
In ac , CBD has been ound o supp ess eac i e gliosis and escue neu ogenesis in he DG o a s injec ed
wi h A
β
1-42 in a PPAR
γ
-dependen manne , likely h ough inac i a ion o GSK-3
β
and subsequen escue
o Wn /
β
-ca enin pa hway, an impo an egula o o AHN [
218
,
320
,
330
,
331
]. Adminis a ion o MDA7,
a po en CB2R selec i e agonis , o AD ansgenic amyloid p ecu so p o ein/p esenilin 1 (APP/PS1)
mice was obse ed o educe mic ogliosis, p omo e A
β
clea ance, es o e memo y pe o mance, synap ic
plas ici y and Sox2 exp ession, a ansc ip ion ac o exp essed by NSCs in he DG [
318
,
332
]. Likewise,
AEA was shown o enhance No ch-1 signaling, a known modula o o AHN, which was impai ed by A
β
in cul u ed neu ons [331,333].
A no ewo hy pa allelism can be made be ween a dose-dependen e ec o ∆9-THC on memo y
and neu ogenesis, whe e low concen a ions o he compound appea o imp o e memo y unc ion
and p omo e AHN, while highe doses seem de imen al ( ecen ly e iewed in [
334
]). Addi ionally,
gi en he ele a ed densi y o cannabinoid ecep o s in he hippocampus and he ele ance o he ECS
in egula ing AHN, i becomes e iden ha he he apeu ic alue o cannabinoids o AD pa hology
may ely on es o ing abe an neu ogenesis [335].
Al hough p eclinical e idence has been suppo i e o he adminis a ion o cannabinoids o
amelio a e AD pa hology, a clinical bene i emains o be assessed due o he limi ed numbe o clinical
ials, wi h sho du a ion and low numbe o subjec s, ha ail o e alua e cogni i e pa ame e s,
as well as bioma ke s o neu odegene a ion [
281
,
336
]. In addi ion, u u e s udies a e needed o
assess long- e m sa e y and e ec i eness o na u al and syn he ic cannabinoids, speci ically in olde
indi iduals wi h AD [
280
,
336
]. Impo an ly, he e is a p essing need o a be e comp ehension o
he unde lying mechanisms conce ning he in e ac ion o cannabinoids in AD and hippocampal NSC
modula ion, namely using speci ic neu ogenic ma ke s.
Molecules 2019,24, 1350 20 o 59
5.2.2. Pa kinson’s Disease
PD is cha ac e ized by a p og essi e degene a ion and subsequen loss o DA neu ons in he
subs an ia nig a pa s compac a (SN) [
337
]. These neu ons compose he b ain mo o sys em, being
esponsible o he ini ia ion o mo emen and he ewa d pa hway, by inne a ion o he s ia um [
338
].
The p esence o Lewy bodies, which a e mainly o med o alpha-synuclein (
α
Syn) agg ega es,
ha e been iden i ied as a p e equisi e o he pos -mo em diagnosis o bo h he p e-symp oma ic
and symp oma ic phases o he pa hological p ocess unde lying PD. These agg ega es ha e been
iden i ied as belonging o wo dis inc ca ego ies, he b ains em- and he co ical-de i ed, wi h he la e
ype being mo e s ongly immuno eac i e o
α
Syn [
339
–
341
]. Symp oma ically, PD is a p og essi e
mo emen diso de ha causes muscle igidi y, emo s, b adykinesia and shu ling gai [
342
]. I can
also cause demen ia, especially in ad anced s ages [
338
]. The mo o dys unc ions, which a e he main
ea u e in PD, become symp oma ic when
≈
60% o neu ons a e al eady los [
341
]. Al hough in he
as majo i y o cases PD is idiopa hic, epidemiological e idence sugges s ha en i onmen al oxins
such as pes icides inc ease PD isk [
340
,
343
]. Howe e , in some cases, PD is associa ed wi h inhe i ed
mu a ions in PD- ela ed genes, such as
α
-Synuclein (SNCA), pa kin (PARKIN), PTEN-induced pu a i e
kinase p o ein 1 (PINK1), ubiqui in ca boxyl- e minal es e ase L1 (UCH-L1) and leucine- ich epea
kinase 2 (LRRK2) [
344
]. Cu en he apeu ics o PD ely mos ly on he use o pha macological agen s,
mainly h ough he use o L-DOPA, a dopamine p ecu so [
345
]. These a e o en used o imp o e
mo o symp oma ology o PD pa ien s, ende ing no e ec i e cu e o PD. The e o e, he de elopmen
o new s a egies has been he ocus o cu en PD esea ch.
Ta ge ing he ECS may p o e as an al e na i e he apy o imp o e mo o symp oms, as PD
pa ien s epo ed an amelio a ion in b adykinesia, accompanied by a educ ion in muscle igidi y and
emo s a e cannabinoid in ake [
346
]. These epo s a e suppo ed by h ee majo pieces o e idence.
Fi s , he basal ganglia and ce ebellum, b ain a eas esponsible o he con ol o mo emen , which a e
highly a ec ed in PD, exp ess CB1R, CB2R and TRPV1R [
347
–
349
]. Second, i has been shown ha
mo o ac i i y is ep essed by he s ong inhibi o y ac ion p omo ed by a a ie y o cannabinoids,
which a e esponsible o ine- une he ac i i y o a ious classical neu o ansmi e s [
350
–
353
]. Finally,
e idence shows ha ECS signaling is al e ed in he basal ganglia o humans and in animal models o
PD [
354
–
356
]. These clinical-based e idence a e suppo ed by obus p e-clinical da a which indica es
ha he ECS has a neu op o ec i e ole in PD [
357
,
358
]. One s udy, using a o enone-induced a
model o PD supplemen ed wi h
β
-ca yophyllene (BCP), a na u ally occu ing CB2R agonis , showed
a dec ease in he le els o p oin lamma o y cy okines and in lamma o y media o s. These esul s
we e u he suppo ed by an inc ease in y osine hyd oxylase immuno eac i i y, which illus a ed he
escue o he DA neu ons and a educ ion in he ac i a ion o glial cells [359].
In human PD pos -mo em s udies, he endogenous pool o adul NSCs was shown o be
signi ican ly a ec ed, speci ically in he SGZ, sugges ing a po en ial e ec o dopamine on NSC
p oli e a ion and su i al, as e iewed by [
161
,
360
]. New e idence sugges s ha adul NSCs a e
also impai ed in animal models o PD, suppo ing da a om human s udies. Al hough he p ecise
mechanisms and e ec s o hese changes a e no ye ully unde s ood,
α
Syn and aging we e shown o
dec ease adul neu ogenesis h oughou he se e al s ages o PD [361–363].
One o he ea lies s ages o PD is cha ac e ized by a non-mo o symp om, namely hyposmia o
anosmia, which is he loss o he sense o smell, being epo ed in 90% o pa ien s [
364
]. Al e a ions in
ol ac ion in PD seem o be ela ed wi h changes in cen al ol ac o y p ocessing, which could be
explained by
α
Syn pa hology being p esen in he ol ac o y bulb long be o e Lewy bodies a e de ec ed
in he SN [
341
]. In ac , neu ogenesis in he SVZ and ol ac o y bulb was shown o be impai ed in a
ansgenic mouse model exp essing he human
α
Syn ca ying he A30P mu a ion, whe e signi ican ly
ewe newly gene a ed neu ons we e obse ed in he ol ac o y bulb [
365
]. O he s udies, using he
Pa kinson 6-hyd oxydopamine (6-OHDA) a model ha e shown ha 6-OHDA induced SN DA
degene a ion and had a majo impac on SGZ neu ogenesis [
366
,
367
]. These epo s sugges ha
dopamine deple ion educes NSC p oli e a ion and consequen ly adul neu ogenesis [368].
Molecules 2019,24, 1350 21 o 59
The e o e, po en ia ing he in insic pool o NSCs has been p oposed as an al e na i e po en ial
PD he apy. Se e al s udies, wi h con adic o y indings, ha e been ocusing on s imula ing he
p oduc ion o DA neu ons om he SVZ and SGZ. In ac , i was shown ha he adminis a ion o
D1 and D3 ecep o agonis s in he 6-OHDA a model, p oduced an inc ease in SGZ and SVZ cell
p oli e a ion, espec i ely [
367
,
369
]. Adding o ha , a D3 ecep o agonis also inc eased DA newbo n
neu ons in he SN, leading o he imp o emen o mo o impai men s [
369
]. Ano he s udy ailed o
induce SN DA neu ogenesis using he D2/D3 ecep o agonis p amip exole, howe e i p omo ed
ol ac o y bulb DA neu ogenesis [
370
]. Ano he g owing s a egy is he use o human plu ipo en
s em cells o induce DA di e en ia ion. These can be de i ed om ea ly p e-implan a ion emb yos
(emb yonic s em cells, ESCs) o by ep og amming adul soma ic cells (induced plu ipo en s em cells,
iPSCs), and hen di e en ia ed in o midb ain DA neu ons using ecen ly de eloped p o ocols [
371
,
372
].
Howe e , b ain implan a ion o hese cells equi es in asi e su gical echniques and gene a es side
e ec s (e.g., g a -induced dyskinesias) wi h signs o disease- ela ed pa hology in he ansplan ed cells
being isible yea s a e implan a ion [373–375]. A cannabinoid induc ion o DA di e en ia ion om
NSCs is s ill unde deba e [
207
,
215
]. One ecen s udy compa ed AEA wi h
∆9
-THC and concluded
ha , using highe doses o hese compounds, he unc ional ma u a ion and DA speci ica ion om
human co d blood-de i ed iPSCs was signi ican ly comp omised [207].
To conclude, in PD, i has been shown in se e al s udies wi h bo h human pos -mo em samples
and animal models ha bo h neu ogenic niches a e signi ican ly impai ed by
α
Syn pa hology o DA
deple ion [
360
,
361
]. Replenishing he DA neu onal loss has been p o ing a challenge o he scien i ic
communi y, whe he by using he endogenous pool o NSCs, o by a ge ing he ECS, o p omo e
neu ogenesis a speci ic and selec i e imepoin s. The ECS may s ill be applied clinically in o de o
amelio a e PD symp oma ology due o he a o emen ioned neu op o ec i e p ope ies o cannabinoids
and he e o e imp o ing he quali y o li e o PD pa ien s [358,376,377].
5.2.3. Mul iple Scle osis
MS is one o he mos ecu en diso de s o he CNS. Despi e i s unknown e iology, an immune
esponse and consequen in il a ion o immune cells in o he CNS oge he wi h demyelina ing e en s
culmina es in oligodend ocy e loss and neu onal degene a ion. Some o he esul ing symp oms a e
spas ici y, emo s, a axia, bladde dys unc ion and neu opa hic pain, wi h a high impai men o he
quali y o li e o he pa ien [
378
–
380
]. MS pa ien s ha consumed cannabis epo ed elie ega ding
se e al o hese symp oms, highligh ing a possible ole o cannabinoids in MS [
380
–
385
]. Fu he mo e,
he neu op o ec i e e ec s o hese molecules in MS has been ho oughly desc ibed in he li e a u e,
since hey a e able o diminish oligodend ocy e dea h and inc ease emyelina ion whils ha ing an
an i-in lamma o y ole [
231
,
386
,
387
]. Changes in eCB le els and also in he le els o i s ecep o s and
deg ading enzymes, FAAH and MAGL, we e obse ed bo h in blood and pos -mo em b ain samples
o MS pa ien s and in animal models o MS, such as he expe imen al au oimmune encephalomyeli is
(EAE) model, in di e en s ages o disease [379,383,388–393].
S udies using EAE-induced mice whe e CB1Rs and CB2Rs we e gene ically dele ed o
pha macologically inhibi ed show ele a ed neu odegene a ion and poo e an i-in lamma o y
esponses accompanied by an inc ease in EAE se e i y and mo o impai men [
379
,
386
,
394
–
396
].
The po en ial a ge s o ECS modula ion in MS, namely he deg ading enzymes and anspo e s
which ac i ely pa icipa e in his mechanism by con olling he le els o eCBs ha e been a ma e o
s udy [
380
,
397
–
399
]. Howe e , he exac mechanisms o he ac ions o cannabinoids in MS a e s ill
no o ally known.
Using he Theile mu ine encephalomyeli is i us-induced demyelina ing disease (TMEV-IDD)
mice, i was possible o obse e ha he modula ion o he ECS by inhibi ion o AEA up ake
esul ed in an imp o emen o mo o pe o mance, educ ion o mic oglial/mac ophage ac i a ion
and p oin lamma o y cy okine elease, accompanied by an inc ease in eCB signaling [400].

Molecules 2019,24, 1350 22 o 59
Recen ly, i has been shown ha CBD a enua es EAE pa hology by ac i a ing an i-in lamma o y
myeloid-de i ed supp esso cells in he pe iphe y, o by modula ing he inc ease o an i-in lamma o y
and dec ease o p oin lamma o y cy okines, bo h
in i o
and
in i o
[
401
,
402
]. Addi ionally,
ea men wi h WIN 55,212-2, a CB1R/CB2R non-selec i e agonis , was ound o a enua e he
in e ac ion be ween leukocy es and endo helial cells, which is necessa y o immune cells o in il a e
he CNS, he e o e inhibi ing in il a ion. Mo eo e , by using selec i e CB1R and CB2R an agonis s,
i was obse ed ha he e ec on leukocy e a icking exe ed by cannabinoids is igge ed by CB2R
ac i a ion [
403
,
404
]. Fu he mo e, as i is in ima ely- ela ed wi h immune esponses, CB2R selec i e
ac i a ion was shown o imp o e EAE pheno ype by dec easing disease se e i y and incidence [
405
].
Addi ionally, he accumula ion o CD4
+
T cells in he b ain and spinal co d is also dec eased in hese
animals, wi h a esponse depending on he ime o adminis a ion, a an ea ly o la e imepoin o
disease cou se [405].
Th oughou he yea s, nume ous clinical ials wo ldwide ha e been using cannabis-based
d ugs in an a emp o ea MS symp oms. Th ee main ac i e p inciples de i ed om cannabis
o mula e hese d ugs: d onabinol (Ma inol
®
), a syn he ic isome o
∆9
-THC, nabilone (Cesame
®
),
a syn he ic analogue o
∆9
-THC and nabiximols (Sa i ex
®
), a 1:1 mix o
∆9
-THC and CBD [
380
].
Sa i ex
®
consis s o an o al sp ay app o ed in some Eu opean coun ies and Canada o he ea men
o spas ici y and pain elie in MS pa ien s, wi h mild- o-mode a e side e ec s ha occu sca cely
in pa ien s [
379
,
380
,
406
–
416
]. Ne e heless, no ial has shown a slowe disease p og ession in MS
pa ien s p esc ibed wi h THC-based d ugs and, hence, he e a e s ill no e idence o i s neu op o ec i e
e ec in humans [379,417,418].
Concomi an ly, in MS he e is myelin damage and oligodend ocy e loss, and hus, inding new
mechanisms o p omo e bo h e-myelina ion and OPC di e en ia ion, ei he om p ecu so s p esen
in he b ain pa enchyma o de i ed om SVZ NSCs is c ucial, since OPCs a e able o mig a e
and pa ially emyelina e lesioned a eas [
249
,
419
–
421
]. Cells om he oligodend oglial lineage a e
di ec ly modula ed by cannabinoids in dis inc ma u a ion s ages, anging om he egula ion o OPC
su i al, p oli e a ion, mig a ion and di e en ia ion o he modula ion o ma u e oligodend ocy e
su i al and myelina ing capaci y [
422
,
423
]. Fo ins ance, i has been obse ed ha OPCs exp ess
CB1Rs and CB2Rs and ha cannabinoids p omo e OPC su i al and oligodend ocy e di e en ia ion
h ough he PI3K/Ak /mTORC1 signaling pa hway, which is known o pa icipa e in he myelina ion
p ocess [
229
,
231
,
422
,
424
–
429
]. CBD has also been shown o be a modula o o his pa hway and i s
adminis a ion o EAE mice was shown o dec ease he in il a ion o in lamma o y immune cells in o
he CNS and o p omo e he phospho yla ion o PI3K, Ak and mTOR, oge he wi h he inhibi ion o
MAPK signaling pa hway, leading o an an i-in lamma o y esponse and neu onal su i al [423].
Al hough se e al s udies ha e looked a he ela ionship be ween cannabinoids and
oligodend ocy e di e en ia ion unde in lamma o y-demyelina ing condi ions, he e is s ill a majo
gap conce ning he abili y o SVZ-de i ed NSCs o be modula ed by cannabinoids and di e en ia e
in o OPCs, which could be use ul o MS he apeu ics and should be add essed in u u e s udies [
235
].
5.2.4. Epilepsy
Epilepsy is a neu ological diso de cha ac e ized by a pe sis en p edisposi ion o gene a e
epilep ic seizu es which a e o en associa ed wi h neu obiological, cogni i e, psychological and
social consequences [
430
,
431
]. An epilep ic seizu e can be de ined as an abno mal excessi e and/o
synch onous neu onal ac i i y in he b ain, which ins iga es a ansien beha io al al e a ion,
comp ising a my iad o signs and symp oms (such as loss o awa eness, s i ening, among o he s) [
430
].
Al hough mos pa ien s ha e idiopa hic epilepsy, seizu es can be induced by lesions o insul s ha
impac no mal b ain unc ion and ac i i y. The main causes o epilepsy include lesions o s uc u al
al e a ions, such as s oke, umo , auma ic b ain inju y, in ec ious diseases, me abolic al e a ions,
au oimmune diseases and gene ic mu a ions [
430
,
432
]. Mo e han 500 genes ha e been linked o
Molecules 2019,24, 1350 23 o 59
epilepsy, including 84 genes ha di ec ly cause epilepsies o synd omes wi h epilepsy as one o hei
co e symp oms [433].
Epilep ogenesis is he mul i ac o ial p ocess ha unde lies he de elopmen o spon aneous
seizu es. I occu s be o e and pe sis s beyond he i s unp o oked episode and can p og ess o e
se e al yea s in humans [
430
,
432
,
434
]. The mechanisms behind his p ocess a e s ill no comple ely
unde s ood bu include a widesp ead o al e a ions in bo h neu onal and non-neu onal cells, leading
o molecula and s uc u al changes ha esul in he dys unc ion o neu onal ci cui s [
430
,
434
,
435
].
The main al e a ion is an imbalance be ween exci a ion and inhibi ion in he neu onal ci cui s, h ough
an inc ease in exci a o y neu o ansmission, as well as a dec ease in inhibi o y neu o ansmission,
esul ing in a s a e o con inuous hype exci abili y [436].
Un il ecen ly, epilepsy ea men was p ima ily ocused in s opping seizu es, dis ega ding
he unde lying mechanisms behind he disease. None heless, his pa adigm is changing, wi h
esea ch con e ging in o e o s on inding new an icon ulsan s, wi h bo h neu op o ec i e and
an iepilep ic p ope ies. Acco ding o ecen da a, he ECS and i s cons i uen s may ep esen such
he apeu ic a ge s [
437
,
438
]. In ac , epilepsy o en induces al e a ions in he ECS, pa icula ly a he
le el o CB1R exp ession and p oduc ion o eCBs [
437
]. Indeed, cu en e idence in mice sugges s
ha CB1R exp ession is up egula ed a GABAe gic synapses and down egula ed a glu ama e gic
synapses in epilepsy, al hough no consensus has been eached [
439
,
440
]. Mo eo e , epilepsy in
humans a ec s he p oduc ion o endogenous eCBs by in e e ing wi h he le els o cannabinoid
enzymes like DAGL and MAGL, which is sugges i e o a pi o al ole o cannabinoid one in his
disease [
441
,
442
]. Eme ging clinical e idence, mos ly coming om epidemiological da a and case
epo s, depic s he o e all posi i e e ec s o cannabinoid adminis a ion using a high a io o
CBD:THC in he managemen o esis an epilepsy [
443
–
445
]. Fu he mo e, cannabinoids and hei
endogenous coun e pa s ha e been associa ed wi h epilepsy ea men , wi h se e al s udies using
a ious cannabinoid-based d ugs in animal models o epilepsy [
446
–
451
]. Fo example, ea men wi h
WIN 55,212-2 (a CB1R/CB2R agonis ) was shown o p e en ch onic epilep ic hippocampal damage in
a s by a enua ing he se e i y and equency o spon aneous ecu en seizu es [
452
]. In pa icula ,
s udies using CB1R ligands ha e shown ha he ac i a ion o his ecep o can delay he p og ession o
seizu e se e i y as well as he equency o spon aneous epilep i o m ac i i y [
446
,
447
,
450
]. Mo eo e ,
s udies using condi ional CB1R KO models ha e demons a ed ha eCB signaling plays an impo an
ole in he e mina ion o epilep ic ac i i y, depending on he neu onal subpopula ion, whils ha ing
no impac in he ini ia ion o hype exci abili y [
451
]. Las ly, i has also been shown ha he MAGL
inhibi ion leads o a delay in he de elopmen o gene alized seizu es in he kindling model o empo al
lobe epilepsy [
449
]. Apa om hei in insic an icon ulsan p ope ies, cannabinoids ha e been
shown o po en ia e o he an i-epilep ic d ugs [453–455].
Impo an ly, epilep ic seizu es we e shown o p omo e abe an AHN in he g anula laye ,
cha ac e ized by a ansien inc ease in he p oli e a ion o neu al p ogeni o s, GCL dispe sion,
pe sis ence o hila basal dend i es and ec opic placing o adul -bo n GCs [
430
,
435
]. E idence shows
ha p olonged seizu es induce an inc ease in cell p oli e a ion in he SGZ (up o 5–10 old), las ing o
se e al weeks [
435
,
456
–
458
]. Howe e , app oxima ely h ee o ou weeks a e he pe sis en seizu e
pe iod, p oli e a ion e u ns o baseline le els o e en dec eases o subs an ially lowe a es when
compa ed o con ol animals [
435
,
457
,
459
]. The same has been obse ed in humans, whe e i was
desc ibed ha se e e seizu es du ing ea ly childhood p omp a dec ease in AHN, nega i ely a ec ing
no mal b ain de elopmen and u he p og ession o epilep ogenesis [
460
]. Whe he he mechanism
in pa ien s is simila o hose ound in animal models, i.e., a ansien inc ease in he p oli e a ion o
neu al p ogeni o s ollowed by a educ ion o neu ogenesis, is no known, ins iga ing u he s udies
o add ess his ma e [435,460,461].
The al e a ions in neu ogenesis go beyond cell p oli e a ion, also a ec ing ma u a ion and
mig a ion o adul -bo n neu ons. A e s a us epilep icus, which consis s o a single epilep ic seizu e
las ing mo e han i e minu es o wo o mo e seizu es wi hin a i e-minu e pe iod wi hou eco e y
Molecules 2019,24, 1350 24 o 59
o consciousness, newbo n GCs mig a e owa ds he den a e hilus o he molecula laye ins ead
o in eg a ing in o he GCL, bo h in oden models and pa ien s wi h epilepsy [
457
,
459
,
462
–
464
].
Mo eo e , he co ec ma u a ion o he GCs upon epilep ic s imuli does no occu , being obse ed an
accumula ion o hila basal dend i es, which a e no mally a ea u e o imma u e cells. This abno mal
ma u a ion may be one o he mechanisms unde lying he hype exci abili y o adul -bo n GCs and he
ci cui s whe e hey in eg a e [
465
–
468
]. Impo an ly, cannabinoids, when combined wi h an iepilep ic
d ugs, can inc ease neu ogenesis in he piloca pine mouse model o epilepsy [
469
,
470
]. In ac ,
co-adminis a ion o ACEA, a selec i e CB1R agonis , wi h sodium alp oa e, a classic an iepilep ic
d ug, was shown o signi ican ly inc ease he numbe o p oli e a ing cells in he same model [
469
,
470
].
Howe e , u he s udies a e needed o asce ain whe he his inc ease in neu ogenesis is no abe an
and can con adic he disease symp oms. None heless, hese esul s show p omise by sugges ing ha
NSC modula ion by cannabinoids can be a po en ial a ge in his diso de .
As a o emen ioned, epilepsy ea men is an e ol ing and eme ging opic wi h he sea ch o
new d ugs and he apeu ic a ge s e e inc easing [
471
]. One key aspec ha can be a ge ed is he
seizu e-induced neu ogenesis, which can also help amelio a e he disease como bidi ies [
472
]. Indeed,
a ge ing abe an AHN may educe ecu en seizu es and es o e cogni i e de ici s, namely memo y
impai men [
473
–
475
]. Since i is known ha he ECS can, on one hand, egula e adul neu ogenesis
and, on he o he hand, ha e an impac in epilep ic ea men , u he s udies a e equi ed o in es iga e
he pu a i e mechanisms by which cannabinoids ha e an impac in he ea men o epilepsy. Mo eo e ,
unde s anding how cannabinoid-induced modula ion o NSCs may ha e neu oplas ic e ec s and
whe he his can be used as an an i-epilep ic ea men is highly ele an .
5.2.5. Anxie y/Dep ession
Anxie y and dep ession a e neu opsychia ic condi ions wi h high p e alence wo ldwide, i s
symp oms ange om i i abili y, anhedonia, di icul ies in concen a ing as well as dis u bances in
appe i e, sleep, dec eased p oduc i i y and inc eased suicide isk [476].
Al e a ions a he le el o NSCs, especially in he hippocampus, a e well known co ela es o bo h
anxie y and dep essi e diso de s [
477
]. The ECS is a known modula o y key playe in NSC egula ion,
d ugs a ge ing his sys em induce mood al e a ions [
478
,
479
]. On he o he hand, AHN has been shown o
be equi ed o he e ec s o an idep essan s, sugges ing ha acili a ion o neu ogenesis can be bene icial
o ch onic an idep essan ea men [
480
]. In line wi h his, se e al indings sugges he in ol emen
o cannabinoids in hese neu ogenesis-p omo ed long-las ing an idep essan e ec s [
481
]. Simila o he
ac ions o con en ional an idep essan s, cannabinoid modula ion was shown o p omo e an idep essan
and anxioly ic e ec s [
479
,
482
]. The e o e, in ecen yea s he e has been a ma ked inc ease in he in e es
o using he ECS as a po en ial he apeu ic a ge in hese diso de s [213,481,483,484].
In e es ingly, changes in eCB le els ha e also been epo ed in a ec i e diso de s. The ci cula ing
le els o hese molecules ha e been ound o be diminished in indi iduals diagnosed wi h dep essi e
and anxie y diso de s [
485
,
486
]. Likewise, in animal models o dep essi e-like beha io he e is a
signi ican o e all dec ease in b ain AEA le els, sugges ing an impai men o eCB one [
487
–
489
].
In line wi h his, polymo phisms in he gene encoding o FAAH (FAAH), ha e been linked o
an inc eased isk o dep essi e and anxie y diso de s [
490
,
491
]. Mo eo e , in animal models o
dep essi e-like beha io , es ain s ess induces a signi ican inc ease o FAAH exp ession in
nume ous b ain egions associa ed wi h a ec i e unc ioning [
492
–
494
]. Da a ega ding 2-AG is
less clea : while i was ound o be diminished in he some egions, as a consequence o ch onic
mild s ess (CMS), i has been obse ed o be inc eased in se e al key egions o he limbic sys em
such as he amygdala, in esponse o he same s ess exposu e [
492
–
494
]. In acco dance wi h his
las inding, MAGL exp ession has been ound o dec ease o e ime, in esponse o pe sis en
s ess [
494
]. These esul s ha e led some esea che s o p opose ha 2-AG p oduc ion may be
s imula ed in si ua ions o pe sis en s ess, as a bu e mechanism agains possible s ess-induced
neu onal dys egula ion [494,495].
Molecules 2019,24, 1350 25 o 59
Acu e and in e mi en adminis a ion o CB1R agonis s is known o biphasically modula e
anxie y, in bo h humans and oden s. Low doses a e known o be anxioly ic, and highe doses
anxiogenic [
496
,
497
]. A he beha io le el, acu e adminis a ion o CB1R agonis s such as
∆9
-THC,
CBC, ACEA, HU-210, CP 55,940 and WIN 55,212-2, ha e been mos ly ela ed o imp o emen s in he
pe o mance o animals in se e al beha io al asks, as well as he o e all pheno ype o animal models o
dep essi e-like beha io [
498
–
504
]. In con as , ch onic exposu e o CB1R agonis s ha e been shown o
induce ma ked al e a ions ha a e age- and gende -dependen [
505
,
506
]. Speci ically, epidemiological
da a sugges s ha while adul ch onic use may be a isk ac o o anxie y and dep essi e diso de s,
his dele e ious e ec is no as p onounced as in adolescen s [
507
–
510
]. Indeed, ch onic adolescen
use s ha e been consis en ly ound o ha e a highe isk o being diagnosed wi h anxie y and/o
dep essi e diso de s, and ha his isk is bigge in emales [
511
–
513
]. Cu iously, in animal models,
he opposi e is sugges ed, since in adolescen animals no pe sis ing al e a ions a he le el o anxie y
ha e been ound bu dep essi e-like beha io has been ound o be ma kedly inc eased [
505
,
506
,
514
].
Impo an ly, his las ing impai men in dep essi e-like beha io seems o be la gely es ic ed o
emale animals, and is accompanied by impai men s in hippocampal neu ogenesis, which is e e sed
by ea men wi h he FAAH inhibi o URB597 [
506
,
515
–
517
]. In con as , adul animals ch onically
exposed o po en ull agonis s o cannabinoid ecep o s show pe sis ing anxioly ic and an idep essan
e ec s, along wi h enhanced AHN, unde sco ing he impo ance o age in he long- e m e ec s o
cannabinoids [518–521].
The e ec s o CB1R an agonism/in e se agonism a e much mo e consis en . Despi e some animal
beha io al e idence o anxioly ic- and an idep essan -like e ec s, imonaban (SR141716) and AM251
ha e been well desc ibed as p omo e s o anxie y and dep essi e-like symp oms in bo h oden s and
humans when ch onically adminis e ed [
494
,
522
–
527
]. Indeed, imonaban , ini ially comme cialized
o he ea men o obesi y, was ecalled a e being ela ed o inc eases in dep essi e/anxious
symp oms [
528
]. Addi ionally, in oden s, his compound has been demons a ed no only o p omo e
dep essi e-like beha io , bu also o educe cell p oli e a ion and su i al in he hippocampus [526].
The e is e idence sugges ing ha single nucleo ide polymo phisms in he CB1R coding gene
(CNR1) a e ela ed o an inc eased isk o s ess-p ecipi a ed dep essi e episodes, as well as esis ance
o an idep essan d ugs [
529
,
530
]. In acco dance, hese polymo phisms a e mo e p e alen among
indi iduals diagnosed wi h mood diso de s [491]. In line wi h his, CMS induces a dec ease in CB1R
exp ession in he hippocampus, hypo halamus and s ia um [
489
,
531
]. Fu he mo e, CB1R KO oden s
p esen a cha ac e is ic anxious/dep essi e-like beha io al p o ile, accompanied by a 50% dec ease in
hippocampal NSC p oli e a ion [213,525,532].
Li le esea ch has been published so a on he e ec s o CB2R agonis s on anxie y- and
dep essi e-like beha io s, wi h a ew con adic o y epo s. Some au ho s epo CB2R agonis s
o ha e anxioly ic e ec s (JWH-015 and BCP), o he s epo anxiogenic e ec s (JWH-133), con as ing
wi h o he s ha epo no e ec s (GW405833) [
533
–
538
]. Mo eo e , CB2R agonis s like BCP, JWH-133
and oleamide, may ha e an idep essan -like e ec s, despi e some epo s inding no changes wi h
he ea men (JWH-015) [
533
,
534
,
539
]. Cu iously, gi en he e ec s o CB2R ac i a ion desc ibed
abo e, he e a e epo s showing CB2R an agonis AM630 as ha ing anxioly ic and an idep essan -like
e ec s [538–540].
Likewise, no much is known abou he in ol emen o CB2Rs in he pa hophysiology o
dep essi e and anxie y diso de s. In humans, a s udy ound an associa ion be ween a polymo phism
in he CB2R coding gene (CNR2) and a numbe o psychia ic and immune diso de s, which a e
o en como bidi ies [
541
]. Mo eo e , animals ca ying his polymo phism a e less sensi i e o he
CB2R-media ed e ec s o WIN 55,212-2 and 2-AG, sugges ing a possible link be ween impai ed CB2R
unc ioning and al e ed beha io al pheno ypes [
542
]. In ac , CB2R KO animals p esen inc eased
anxie y- and dep essi e-like beha io s [
543
,
544
]. Simila ly, animals o e exp essing CB2Rs no only
show educed anxious- and dep essi e-like beha io al pheno ypes, bu also a e ac ually esis an o
Molecules 2019,24, 1350 32 o 59
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