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Abstract

Objective: Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. Methods: We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Results: Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Conclusions: Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.
SPECIAL ARTICLE
Biological bases for a possible effect of cannabidiol in
Parkinson’s disease
Nilson C. Ferreira-Junior,
1,2
Alline C. Campos,
1
Francisco S. Guimara
˜es,
1
Elaine Del-Bel,
2
Patrı
´cia M.
da R. Zimmermann,
3
Liberato Brum Junior,
3
Jaime E. Hallak,
4
Jose
´A. Crippa,
4
0000-0001-9520-6746
Antonio W. Zuardi
4
1
Departamento de Farmacologia, Faculdade de Medicina de Ribeira
˜o Preto (FMRP), Universidade de Sa
˜o Paulo (USP), Ribeira
˜o Preto, SP,
Brazil.
2
Departamento de Morfologia Fisiologia e Patologia Ba
´sica, Faculdade de Odontologia de Ribeira
˜o Preto (FORP), USP, Ribeira
˜o Preto,
SP, Brazil.
3
Prati Donaduzzi & Cia Ltda., Toledo, PR, Brazil.
4
Departamento de Neurocie
ˆncias e Cie
ˆncias do Comportamento, FMRP, USP,
Ribeira
˜o Preto, SP, Brazil.
Objective: Current pharmacotherapy of Parkinson’s disease (PD) is palliative and unable to modify
the progression of neurodegeneration. Treatments that can improve patients’ quality of life with fewer
side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic
constituent of cannabis, has received considerable research attention in the last decade. In this
context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and
discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD.
Methods: We searched MEDLINE (via PubMed) for indexed articles published in English from
inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection;
endocannabinoids and basal ganglia; Parkinson’s animal models; Parkinson’s history; Parkinson’s and
cannabidiol.
Results: Few studies addressed the biological bases for the purported effects of CBD on PD. Six
preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of
CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series,
and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor
symptoms.
Conclusions: Additional research is needed to elucidate the potential effectiveness of CBD in PD and
the underlying mechanisms involved.
Keywords: Cannabidiol; CBD; Parkinson; neurodegeneration; neuroprotection
Pathophysiology of Parkinson’s disease
In ‘‘An essay on the shaking palsy’’ (1817), James
Parkinson first described a condition of insidious onset with
a progressive and disabling course characterized by resting
tremor, flexed posture, and festinating gait.
1
Martin Charcot
later added extensive details to Parkinson’s observations,
identifying bradykinesia and rigidity as key symptoms of the
disease.
2
In 1895, Brissaud hypothesized that the sub-
stantia nigra (SN) was the main brain nucleus affected in
Parkinson’s disease (PD),
3
andFriedrichHeinrichLewy
described protein aggregates in brain areas of PD patients,
including the globus pallidus, the dorsal nucleus of the
vagus, and the locus coeruleus.
4
Shortly thereafter, in 1919,
Tretiakoff validated Lewy’s hypothesis by describing the
protein aggregates observed in postmortem brain tissue of
PD patients, which he called Lewy bodies.
5
Pathologically, PD is characterized by early death of
dopaminergic neurons in the SN pars compacta (SNpc),
leading to dopamine deficiency within the basal ganglia
and a movement disorder consisting of the classic
parkinsonian motor symptoms. However, PD is also
associated with multiple non-motor symptoms, some of
which precede motor dysfunction by more than a decade.
The mainstay of PD management is symptomatic treat-
ment with drugs that increase brain dopamine concentra-
tions or directly stimulate dopamine receptors.
As noted above, PD begins years before clinical
diagnosis, involves multiple brain regions, and entails
motor and non-motor symptoms. It is a slow, progressive
neurodegenerative disorder of multifactorial etiology,
resulting from a combination of genetic and environmental
factors. For instance, although still controversial, smokers
are twice as likely to develop PD,
6
caffeine consumers
have a lower incidence of the disease,
7
and association
between obesity and herbicide exposure seems to be a
risk factor for dopaminergic neurodegeneration.
8
From the
genetic standpoint, studies have shown that mutations in
Correspondence: Anto
ˆnio W. Zuardi, Departamento de Neurocie
ˆn-
cias e Cie
ˆncias do Comportamento, Faculdade de Medicina de
Ribeira
˜o Preto, Universidade de Sa
˜o Paulo, Av. Bandeirantes, 3900,
CEP 14049-900, Ribeira
˜o Preto, SP, Brazil.
E-mail: awzuardi@fmrp.usp.br
Submitted Feb 20 2019, accepted Apr 08 2019.
How to cite this article: Ferreira-Junior N, Campos AC, Guimara
˜es
FS, Del-Bel E, Zimmermann PMR, Brum Junior L, et al. Biological
bases for a possible effect of cannabidiol in Parkinson’s disease.
Braz J Psychiatry. 2019;00:000-000. http://dx.doi.org/10.1590/1516-
4446-2019-0460
Brazilian Journal of Psychiatry. 2019 xxx–xxx;00(00):000–000
Brazilian Psychiatric Association
Revista Brasileira de Psiquiatria
CC-BY-NC | doi:10.1590/1516-4446-2019-0460
different genes – such as Parkin, PINK1,DJ-1,LRRK2,
GBA, and ATP13A2 – are implicated in several types of
parkinsonism as well as in PD.
9-11
Hereditary PD is
classified as either dominant or recessive; the majority of
genetically associated cases feature early (rarely, even
juvenile) onset.
11,12
In the literature, the genetic factors associated with PD
have often been related to causal mechanisms such as
oxidative stress, glutamate excitotoxicity, mitochondrial
dysfunction, neuroinflammation, apoptosis, and increased
susceptibility of the dopaminergic neurons of the SNpc to
neurotoxins.
9,10
An important hypothesis proposes that
oxidative stress generates free radicals, such as dopa-
mine quinone, that can react with the cytoplasmic pro-
tein a-synuclein, producing protofibrils that cannot be
degraded by the ubiquitin-proteasome system. These
protofibrils accumulate and generate eosinophilic cyto-
plasmic inclusions (Lewy bodies), causing the death of
dopaminergic neurons in the nigrostriatal pathway.
10,11,13
Although the understanding of the pathophysiology of
PD has improved markedly since its initial characteriza-
tion, an effective pharmacological treatment to prevent or
slow the progression of dopaminergic neuronal degen-
eration has yet to be developed. The pharmacotherapy of
PD continues to be palliative, aiming to restore reduced
dopamine levels in the striatum.
14,15
The standard treat-
ment is based on (S)-2 amino-3-(3,4-dihydroxyphenyl)
propionic acid, also known as levodopa (L-DOPA).
14,15
L-DOPA is considered a safe and effective drug for
reducing the motor symptoms of PD, with only mild side
effects, such as nausea, vomiting, and postural hypoten-
sion.
14,15
However, the long-term efficacy of L-DOPA is
limited by the development of disabling motor complica-
tions such as L-DOPA-induced dyskinesia, a set of abnormal
involuntary movements that include chorea, hemiballismus,
and athetosis.
16
In this context, the search for more effective and
tolerable treatments is imperative. Preclinical research
provides opportunities for the discovery of new PD drugs,
and animal models that mimic some aspects of PD have
been used in an attempt to describe promising candidate
agents. We searched MEDLINE (via PubMed) for indexed
articles published in English from inception to 2019. The
following keywords were used: cannabis; cannabidiol and
neuroprotection; endocannabinoids and basal ganglia;
Parkinson’s animal models; Parkinson’s history; Parkin-
son’s and cannabidiol.
Animal models for the study of Parkinson’s
disease
Toxin-based models
Neurotoxin-based models are useful to understand the
mechanisms underlying the neurobiology of PD and
the dopaminergic neuronal loss observed in PD, through
the use of neurotoxins such as dopamine analogs (e.g.,
6-hydroxydopamine [6-OHDA]), contaminants of synthetic
heroin (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
[MPTP]), herbicides (e.g., rotenone), heavy metals (e.g.,
manganese and iron), and lipopolysaccharide (LPS).
The first substance reported to cause lesions in the
nigrostriatal pathway in rats was 6-OHDA.
17
This toxin
accumulates in the cytosol of neurons and promotes the
formation of hydrogen peroxide, other reactive oxygen
species, and quinines by auto-oxidation.
18
6-OHDA is a
hydrophilic compound and cannot cross the blood-brain
barrier. It is administered by direct injection into the SNpc,
medial forebrain bundle, or striatum, depending on the
objective of the researcher (rate and extent of injury).
19
Even though 6-OHDA has been the most common
model in preclinical research, it is non-selective for dopa-
mine transporters, and is commonly co-administered with
selective noradrenaline uptake blockers to prevent loss
of noradrenergic neurons.
20
Another disadvantage of
6-OHDA use relies on its inability to produce Lewy body-
like inclusions.
21
MPTP is a neurotoxin that is converted into an
intermediate metabolite by the action of monoamine
oxidase B in glial cells, and then oxidized to 1-methyl-
4-phenylpyridinium (MPP+).
22
MPP+has high affinity
for the dopamine transporter, but lower affinity for
norepinephrine and serotonin transporters.
23
Within dopa-
minergic neurons, MPP+is sequestrated into synaptic
vesicles or concentrated within the mitochondria, where
it blocks the electron transport chain.
24
In monkeys,
MPTP administration produces Lewy body-like inclu-
sions, and the susceptibility to MPTP-induced lesions
increases with age.
25
Rotenone is a pesticide that acts by blocking the
mitochondrial electron transport chain, mitosis, and cell
proliferation.
26
Chronic systemic exposure to rotenone in
rats causes many features of PD, including nigrostriatal
degeneration and Lewy body-like inclusions, but this
model is difficult to replicate due to the high mortality
of animals.
26,27
Another pesticide used to study PD is
paraquat, one of the most widely used herbicides in
agriculture.
26
It shares structural similarity to MPP+.
26
Paraquat generates Lewy body-like inclusions,
26
but it
has low specificity for dopaminergic neurons and causes
variable cell death.
26,28
Paraquat has been used in conjunction with manga-
nese ethylene-bis-dithiocarbamate (maneb), a fungicide
which has been shown to potentiate the toxic effects
of paraquat and of MPTP.
26
Results have shown that
maneb may, on its own, decrease locomotor activity
and produce loss of neurons in the substantia nigra.
29
Chronic exposure to maneb produces signs of manga-
nese intoxication,
30
followed by a neurological syndrome
with cognitive, psychiatric, and movement abnormalities
that resemble some clinical features of PD.
31
Maneb
appears to cross the blood-brain barrier and inhibit
mitochondrial complex III.
32,33
The paraquat/maneb
model can induce behavioral and motor impairments,
significant dopamine-related degeneration, and altered
responsiveness to dopamine therapy. Conversely, multi-
ple variants of this animal model have been reported to
evoke neither formation of Lewy bodies nor non-motor
symptoms.
33
Moreover, some nonspecific and undesir-
able peripheral effects are reported, mainly in the lungs
(respiratory distress), which limits utilization of these
toxins.
33
Braz J Psychiatry. 2019;00(00)
2Ferreira-Junior NC et al.
Genetic models
A large genome-analysis study has implicated 28 inde-
pendent variants across 24 loci in the pathogenesis of
familial PD.
31
Five genes associated with familial PD have
been extensively studied and used as genetic models of
PD in rodents: a-synuclein, PINK1, Parkin, DJ-1, and
LRKK2.
26,34,35
Considering that the more prevalent forms
of PD involve several genes and alterations in many gene
functions,
26,36
monogenic models of PD would be expec-
ted to be less successful than toxin-induced models to
evoke loss in the dopaminergic nigrostriatal pathway.
However, genetic models are interesting tools to help to
recognize whether a mutant gene is associated with the
progression of PD in humans, verify the involvement of
unknown genes in the disease, and understand the more
common genetic mechanisms of PD.
26
Several studies have demonstrated the contribution
of genetic factors to PD development. A meta-analysis
evaluated the interaction between the diagnosis of PD
and risk factors. The strongest association with later
diagnosis of PD was found for patients having a first-
degree or any relative with PD, suggesting an increased
risk of PD diagnosis in patients with a family history
of PD.
37
Further convincing evidence for the contribution
of genetic factors to PD was provided by the discovery of
monogenic forms of the disease. The SNCA gene, which
encodes a-synuclein, was the first to be associated with
inherited PD.
38
Mutations in the LRRK2 and Parkin genes
have been associated with dominantly and recessively
inherited PD, respectively.
39,40
Currently, the most sig-
nificant genetic risk factor for developing PD appears
to be a mutation in the GBA gene, which encodes
b-glucocerebrosidase.
40,41
Endocannabinoids and basal ganglia
Preclinical studies have suggested that endocannabinoid
signaling plays an important role in basal ganglia
circuitry.
42-45
Endocannabinoids are neurotransmitters
derived from membrane phospholipids produced on
demand by enzymes expressed throughout the central
nervous system (CNS).
46,47
The main endogenous ligands
are anandamide (AEA) and 2-arachidonoylglycerol (2-
AG).
46,47
Endocannabinoids bind both to subtype 1 (CB
1
)
and2(CB
2
) cannabinoid receptors
46,47
AEA is synthesized
by N-acyl phosphatidylethanolamine phospholipase D
(NAPE-PLD) and degraded by fatty acid amide hydrolase
(FAAH),
46,47
while 2-AG is synthesized by diacylglyce-
rol lipase (DGL) and degraded by monoacylglycerol
lipase.
46,47
In the striatum, CB
1
is expressed at low levels in
glutamatergic terminals and at high levels in GABAergic
neurons in both D1 (substance P) and D2 (enkephalin)
spiny projection neurons.
48
The co-localization of CB
1
and GABAergic interneurons is controversial. Double-
labeling in situ hybridization revealed that neither soma-
tostatinergic nor cholinergic interneurons expressed CB
1
receptors,
49
while GABAergic immunohistochemistry
showed high CB
1
immunoreactivity in the perikarya
and axons of parvalbuminergic interneurons, and low
levels in nitric oxide synthase (NOS)/somatostatin-
positive interneurons.
48
On the other hand, another study
showed that the highest expression of CB1 occurs in
calbindin interneurons, with less expression in parval-
bumin-positive neurons.
50
No CB
1
immunostaining was
found in calretinin or cholecystokinin neurons.
48
AEA synthesized in striatal postsynaptic GABAergic
neurons can act on glutamatergic presynaptic terminals,
51
decreasing glutamate release from cortical areas.
52
Striatal CB
1
receptor stimulation is critical for long-term
depression (LTD) in corticostriatal synapses,
52,53
thus
reducing glutamatergic synaptic effectiveness. Dopami-
nergic neurons do not express CB
1
receptors,
54
but the
endocannabinoid system can interact indirectly with
dopaminergic neurotransmission in the striatum, interfer-
ing with the control of voluntary movements.
55,56
Applica-
tion of cannabinoid agonists to striatal slices produces
either no effect or a decrease in electrical stimulation-
evoked dopamine release,
57,58
while systemic adminis-
tration of a CB
1
agonist leads to inhibition of dopamine
release evoked by pulse-train stimulation of the medial
forebrain bundle.
59
CB
1
receptors in the striatum mediate motor deficits
induced by cannabinoids.
60
The main psychoactive com-
ponent of cannabis, D9-tetrahydrocannabinol (THC), exerts
its effects in the CNS via activation of CB
1
receptors.
61
Consistent with effects on basal-ganglia function, CB
1
activation by THC (or other cannabinoid agonists) alters
motor performance in a dose-dependent manner, fluctuat-
ing from increased mobility
62,63
to inhibition of sponta-
neous activity,
64,65
irregular locomotion, or even immobility
(catalepsy).
62,66,67
On the other hand, CB
1
receptor activation dampens
amphetamine-induced hyperlocomotion, as well as the
rise in dopamine and glutamate release in the striatum.
68
Striatal CB
1
receptors also decrease GABAergic input to
dopaminergic neurons of the SNpc, thus modulating the
firing activity of these neurons.
69
Accordingly, it has been
accepted that the endocannabinoid system modifies striatal
functioning and interferes with motor control.
Cannabidiol and neuroprotection
Unlike THC, which elicits subjective effects by binding at
CB
1
receptors, cannabidiol (CBD), the main non-psycho-
tomimetic component of Cannabis sp., has low affinity to
cannabinoid receptors.
61,70
CBD was isolated by Adams
et al. in 1940
71
and its structure was identified 23 years
later by Mechoulam & Shvo.
72
The concentration of CBD
in cannabis is highly variable, depending on plant pheno-
type, cultivation conditions, and which part of the plant is
used to obtain the extract.
73
CBD exerts a variety of effects in laboratory animals
and humans, including sedative/hypnotic,
74,75
anticonvul-
sant,
76,77
neuroprotective,
78,79
cardiovascular,
80,81
and
anti-inflammatory.
78,82
These actions do not seem to be
dependent on cannabinoid receptors.
61
Moreover, it is not
completely understood whether these effects are related
to CBD or to other organic compounds present in Cannabis
extracts, such as myrcene and other terpenoids.
83
Braz J Psychiatry. 2019;00(00)
Effectiveness and mechanisms of CBD in Parkinson 3
Therefore, more studies using pure CBD are needed to
confirm the effects of CBD in animals and humans.
CBD binds to cannabinoid receptors only at micromolar
concentrations (X10 mM),
61
acting as a low-potency
agonist, inverse agonist, antagonist, or even as an allo-
steric modulator of the cannabinoid CB1 receptor.
61,84,85
Some CBD effects are antagonized by CB
1
receptor
inverse agonists,
61
suggesting this drug may exert
‘‘indirect agonism’’ at CB
1
receptors. Studies show that
CBD can increase AEA concentration by blocking the
AEA membrane transporter (AMT) or the FAAH enzyme,
which catalyzes AEA hydrolysis.
61,86,87
CBD also enhances
membrane fluidity,
88
increases 2-AG levels,
89
and upregu-
lates CB
1
receptor expression.
90
Several studies have demonstrated the neuroprotective
properties of the CBD in different conditions, such as
newborn hypoxic-ischemic encephalopathy,
79
chronic
cerebral hypoperfusion,
91
neonatal iron overload,
92
and
kainic acid-induced seizures.
93
The neuroprotective prop-
erties of CBD do not appear to depend on direct activation
of CB
1
receptors,
94
but can be related to a reduction in
glutamate excitotoxicity and oxidative stress,
79
neuroin-
flammation decrease,
91
anti-apoptotic action,
92
or mod-
ulation/polarization of glial cells.
93
In spite of the involvement of CB
2
receptors in the
neuroprotective effect of CBD in a model of hypoxic-
ischemic in newborn mice,
79
the possibility of its direct
action at these receptors remains controversial.
86,87
CBD
also interacts with several other targets.
61,87
One of them
is a family of ionotropic receptors permeable to mono-
valent cations and calcium named transient receptor
potential vanilloid (TRPV).
87,95
At low concentrations (sub-
micromolar scale), CBD binds to equilibrative nucleoside
transporter (ENT), transient receptor potential melastatin
type 8 (TRPM8), serotonin 1A receptor (5-HT1A), glycine
receptors A1 and A3, and transient receptor potential
ankyrin type-1 (TRPA1).
46,61
On the other hand, at high
concentrations (micromolar scale), CBD activates TRPV2,
TRPV3, and TRPV4 receptors and peroxisome proliferator-
activated receptor-g(PPAR-g).
61,87
CBD is also an
antagonist of the orphan receptor GPR55
96
and it may
also increase intracellular calcium in physiological con-
ditions but decrease it under high neuronal excitability
conditions.
61,87
Cannabidiol and Parkinson’s disease
Preclinical studies
Several in vitro experiments have demonstrated promis-
ing neuroprotective effects of CBD in PD models. In one
of these models, using PC12 and SH-SY5Y cells treated
with MPP+, CBD increased cell viability, differentiation,
and the expression of axonal (GAP-43) and synaptic
(synaptophysin and synapsin I) proteins. These neuro-
protective effects depended on the activation of tropo-
myosin receptor kinase A (TrkA) receptors.
97
CBD also
protected SH-SY5Y cells against LPS- and b-amyloid-
induced decreases in cell viability, while increasing the
viability of SH-SY5Y cells incubated with conditioned media
derived from microglia previously activated with LPS.
98
In another study, CBD blunted ATP-induced increases in
intracellular calcium and LPS-evoked nitrite generation
in both N13 microglial cells and rat primary microglia.
The authors suggested that the reduction of microglial cell
activation promoted by CBD depends on both cannabinoid
and adenosine receptors.
99
In vivo studies, however, have produced conflicting
results. A neurotoxic model of PD using MPTP demon-
strated that administration of CBD (5 mg/kg) for 5 weeks
did not reduce motor deficits or dopaminergic neuronal
loss in the nigrostriatal pathway.
100
On the other hand,
daily administration of CBD (3 mg/kg) for 14 days
decreased both dopamine depletion and tyrosine hydro-
xylase expression within the striatum of rats that received
6-OHDA.
101
These neuroprotective effects were asso-
ciated with an upregulation of mRNA levels of Cu
2+
/Zn
superoxide dismutase, a key enzyme necessary for the
endogenous control of oxidative stress.
102
Beyond these neuroprotective effects, one study
suggested a putative antidyskinetic effect of CBD in
hemiparkinsonian mice chronically treated with L-DOPA.
Of note, although CBD administration does not reduce
L-DOPA-induced dyskinesia, when combined with the
TRPV1 receptor antagonist capsazepine, a significant
antidyskinetic effect was observed (capsazepine alone
also failed to decrease dyskinesia).
103
CBD also pre-
vented cataleptic behavior induced by repeated admin-
istration of reserpine
91
or haloperidol. In the latter case,
CBD also produced a reduction in c-Fos protein expres-
sion in the dorsal striatum via activation of 5-HT1A
serotonin receptors.
104,105
Clinical studies
An open-label pilot study conducted in PD patients
showed that oral doses of CBD ranging from 150-400
mg/day, combined with classic antiparkinsonian agents,
reduced psychotic symptoms evaluated by different
scales (the Brief Psychiatric Rating Scale [BPRS] and
the Parkinson Psychosis Questionnaire [PPQ]) with no
influence on cognitive and motor signs and no severe side
effects.
106
In a case series with four patients, CBD
reduced the frequency of events related to REM sleep
behavior disorder.
107
In a subsequent clinical trial, 300 mg/day of CBD
improved mobility, emotional well-being, cognition, com-
munication, and body discomfort compared to placebo.
The authors suggest that this effect might be related to
the anxiolytic, antidepressant, and antipsychotic proper-
ties of CBD.
108
SinceCBDiswelltoleratedinhumans,
these positive effects suggest it could be a promising
alternative for PD pharmacotherapy.
Therefore, double-blind, placebo-controlled, rando-
mized trials with larger samples of patients with PD are
needed to elucidate the possible effectiveness and
mechanisms involved in the therapeutic potential of
CBD in this movement disorder. This will also include the
putative effects of CBD in preventing L-DOPA-induced
severe side effects and preventing PD progression.
Additionally, studies conducted specifically to evaluate
the safety profile of CBD in patients with PD (including
Braz J Psychiatry. 2019;00(00)
4Ferreira-Junior NC et al.
long-term safety), possible interactions with other anti-
parkinsonian drugs, and possible side effects, as well
as the therapeutic window for motor and non-motor PD
symptoms are also required.
Acknowledgements
This study was supported in part by grants from
Fundac¸a
˜odeAmparoa
`Pesquisa do Estado de Sa
˜o
Paulo (FAPESP; grant 2015/05551-0 awarded to ACC);
Conselho Nacional de Desenvolvimento Cientı
´fico e
Tecnolo
´gico (CNPq); Coordenac¸a
˜odeAperfeic¸oamento
de Pessoal de Nı
´vel Superior (CAPES); Fundac¸a
˜ode
Apoio ao Ensino, Pesquisa e Assiste
ˆncia (FAEPA),
Hospital das Clı
´nicas, Faculdade de Medicina de
Ribeira
˜oPreto,UniversidadedeSa
˜oPaulo(USP);
Nu
´cleo de Apoio a
`Pesquisa em Neurocie
ˆncia Aplicada
(NAPNA), USP; and Instituto Nacional de Cie
ˆncia e
Tecnologia Translacional em Medicina (INCT-TM;
CNPq/FAPESP).
FSG, JAC, and AWZ are recipients of CNPq 1A
productivity fellowships. ACC is recipient of CNPq 2
productivity fellowship. ED-B is recipient of CNPq
productivity fellowship. JAC has received travel support
from and is medical advisor of SCBD Centre; and has
received a grant from University Global Partnership
Network (UGPN) – ‘‘Global priorities in cannabinoid
research excellence.’’ JAC is member of the international
advisory board of The Australian Centre for Cannabinoid
Clinical and Research Excellence (ACRE), funded by the
National Health and Medical Research Council through
the Centre of Research Excellence).
Disclosure
JAC, FSG, and AWZ are co-inventors (Mechoulam R,
Crippa JA, Guimaraes FS, Zuardi A, Hallak, JE, and
Breuer A) of the patent ‘‘Fluorinated CBD compounds,
compositions and uses thereof. Pub. No.: WO/2014/
108899. International Application No.: PCT/IL2014/
050023’’ Def. US no. Reg. 62193296; July 29, 2015;
INPI on August 19, 2015 (BR1120150164927). Uni-
versidade de Sa
˜o Paulo has licensed the patent to
Phytecs Pharm (USP Resolution no. 15.1.130002.1.1).
USP has an agreement with Prati-Donaduzzi (Toledo,
Brazil) to ‘‘develop a pharmaceutical product containing
synthetic CBD and prove its safety and therapeutic
efficacy in the treatment of epilepsy, schizophrenia,
Parkinson’s disease, and anxiety disorders.’’ The other
authors report no conflicts of interest.
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Effectiveness and mechanisms of CBD in Parkinson 7
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In this work, 2-AG was successfully detected in human plasma samples using a new sandwich-type electrochemical immune device based on poly-β-cyclodextrin P(β-CD) functionalized with AuNPs-DDT and toluidine blue. The P(β-CD) ensured the bioactivity and stability of the immobilized 2-AG antibody by providing a broad surface for the efficient immobilization of the biotinylated antibody. To complete the top section of the immunosensor (reporter), an HRP-conjugated antibody of 2-AG (secondary antibody (Ab2)) was attached to the surface of a glassy carbon electrode (GCE) modified by P(β-CD), as well as a primarily biotinylated antibody (Ab1). The biosensor fabrication process was monitored using field-emission scanning electron microscope (FE-SEM) and EDS methods. Using the differential pulse voltammetry technique, the immunosensor was utilized for detection of 2-AG in real samples. The suggested interface increased the surface area, which allowed for the immobilization of a large quantity of anti-2-AG antibody while also improving biocompatibility, stability, and electrical conductivity. Finally, the suggested immunosensor’s limit of quantitation was determined to be 0.0078 ng/L, with a linear range of 0.0078 to 1.0 ng/L. The results showed that the suggested bioassay can be utilized for diagnosis of 2-AG in clinical samples as a unique and ultrasensitive electrochemical biodevice.
... 14 Many preclinical studies have shown the properties of CBD as a potential anxiolytic, panicolytic, anticompulsive, and antidepressant. 6 One clinical trial found a CBD intake of 300 mg/d in patients with PD improved mobility, emotional well-being, cognition, communication, and body discomfort compared with placebo, 15 likely attributed to the anxiolytic, antidepressant, and antipsychotic properties of CBD. 16 Although more research has been done for the use of CBD in patients with depression, few studies have specifically examined its use in PD. 17 Because the pathophysiology of depression in PD and non-PD considerably differ, the alternative strategies in non-PD may not be as effective in PD. 9 Although most recent studies reported a beneficial effect of CBD in nonmotor symptoms of PD, that was from escalated dosage of CBD. ...
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Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the decrease in dopaminergic neurons in the brain leading to motor and nonmotor symptoms. With the increased availability of cannabidiol in the United States and interest in the PD community for PD-related symptom management in complementary to pharmacologic treatment, this review provides nurse practitioners with useful information on existing studies and regulatory considerations on the implication of cannabidiol in PD.
... Affirmed neuroprotective properties of select CBs have resulted in ample suggestion for therapeutic use of these compounds in neurodegenerative diseases, including Alzheimer's disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, as well as PD (Cooray et al., 2020;Manera & Bertini, 2021;Pérez-Olives et al., 2021;Rodríguez-Cueto et al., 2021). In relation to the latter, biphasic alteration of CB signaling during PD progression as well as the neuromodulatory role of the endocannabinoid system (ECS) in cause, symptomatology, and treatment of PD has been reviewed (Behl et al., 2020;Ferreira-Junior et al., 2020;Junior et al., 2020). Specifically, ECs regulate the basal ganglia neuronal circuitry, synaptic plasticity, and motor functions via communication with dopaminergic as well as other neurotransmitter systems such as glutamatergic and GABAergic systems. ...
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Dyskinesia or abnormal involuntary movement is an unfortunate consequence of long-term therapy with L-DOPA, a gold standard for the treatment of Parkinson’s disease (PD). L-DOPA-induced dyskinesia (LID) is affected by age of onset, duration and severity of PD, L-DOPA dose, as well as gender. The main treatment modality is reduction of L-DOPA dose. Although administration of apomorphine, amantadine, and clozapine may be helpful, more effective pharmacotherapies are urgently needed. Recent advances in our understanding of the pathophysiology of LID have led to suggestions of novel interventions. In this chapter, three classes of drugs, nicotinic receptor agonists, glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists, and cannabinoid receptor agonists, where their effectiveness in preclinical studies has been established, will be discussed in detail.
... neuronal protection as Alzheimer's and Parkinson's diseases. 102,103 Moreover, the use of intranasal and intraperitoneal CBD in animal models of DMT1 was associated with reduced microglia cell density in the dorsal spinal cord and lesser NeP in the DPN. 74 There is a large body of evidence that cannabinoids are effective painkillers in cases of acute, inflammatory, and NePs. ...
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Introduction: Cannabinoids such as ▵-9-THC and CBD can downregulate the immune response by modulating the endocannabinoid system. This modulation is relevant for the treatment of prevalent autoimmune diseases (ADs), such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), diabetes mellitus type 1 (DMT1), and rheumatoid arthritis (RA). These conditions require new therapeutic options with fewer side effects for the control of the autoimmune response. Objective: to conduct a literature review of preclinical scientific evidence that supports further clinical investigations for the use of cannabinoids (natural or synthetic) as potential immunomodulators of the immune response in ADs. Methodology: A systematic search was carried out in different databases using different MeSH terms, such as Cannabis sativa L., cannabinoids, immunomodulation, and ADs. Initially, 677 journal articles were found. After filtering by publication date (from 2000 to 2020 for SLE, DMT1, and RA; and 2010 to 2020 for MS) and removing the duplicate items, 200 articles were selected and analyzed by title and summary associated with the use of cannabinoids as immunomodulatory treatment for those diseases. Results: Evidence of the immunomodulatory effect of cannabinoids in the diseases previously mentioned, but SLE that did not meet the search criteria, was summarized from 24 journal articles. CBD was found to be one of the main modulators of the immune response. This molecule decreased the number of Th1 and Th17 proinflammatory cells and the production of the proinflammatory cytokines, interleukin (IL)-1, IL-12, IL-17, interferon (IFN)-γ, and tumor necrosis factor alpha, in mouse models of MS and DMT1. Additionally, new synthetic cannabinoid-like molecules, with agonist or antagonist activity on CB1, CB2, TRPV1, PPAR-α, and PPAR-γ receptors, have shown anti-inflammatory properties in MS, DMT1, and RA. Conclusion: Data from experimental animal models of AD showed that natural and synthetic cannabinoids downregulate inflammatory responses mediated by immune cells responsible for AD chronicity and progression. Although synthetic cannabinoid-like molecules were evaluated in just two clinical trials, they corroborated the potential use of cannabinoids to treat some ADs. Notwithstanding, new cannabinoid-based approaches are required to provide alternative treatments to patients affected by the large group of ADs.
... In 2020, a Brazilian team published a paper discussing the biological basis for the potential role of CBD, as well as the team's preclinical and clinical studies of CBD in Parkinson's disease. The three clinical studies include open label studies (six patients), case series (four patients), and randomized controlled trials (twenty-one patients) (Zuardi et al., 2009;Chagas et al., 2014;Ferreira-Junior et al., 2020). Although these studies have shown beneficial results, they are limited by the small sample size and short follow-up time, which make the results inconclusive. ...
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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two typical neurodegenerative diseases that increased with aging. With the emergence of aging population, the health problem and economic burden caused by the two diseases also increase. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) signaling pathway regulates signal transduction and biological processes such as cell proliferation, apoptosis and metabolism. According to reports, it regulates neurotoxicity and mediates the survival of neurons through different substrates such as forkhead box protein Os (FoxOs), glycogen synthase kinase-3β (GSK-3β), and caspase-9. Accumulating evidences indicate that some natural products can play a neuroprotective role by activating PI3K/AKT pathway, providing an effective resource for the discovery of potential therapeutic drugs. This article reviews the relationship between AKT signaling pathway and AD and PD, and discusses the potential natural products based on the PI3K/AKT signaling pathway to treat two diseases in recent years, hoping to provide guidance and reference for this field. Further development of Chinese herbal medicine is needed to treat these two diseases.
... Limited research has been done on CBDs effect on Parkinson's disease symptoms, though the current evidence suggests it can improve the non-mobility related symptoms, there is contradicting evidence on its effects on mobility and cognition symptoms [87]. Further studies need to be conducted to determine the true extent of CBD treatment on Parkinson's disease. ...
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Industrial hemp (Cannabis sativa L., Cannabaceae) is an ancient cultivated plant originating from Central Asia and historically has been a multi-use crop valued for its fiber, food, and medicinal uses. Various oriental and Asian cultures kept records of its production and numerous uses. Due to the similarities between industrial hemp (fiber and grain) and the narcotic/medical type of Cannabis, the production of industrial hemp was prohibited in most countries, wiping out centuries of learning and genetic resources. In the past two decades, most countries have legalized industrial hemp production, prompting a significant amount of research on the health benefits of hemp and hemp products. Current research is yet to verify the various health claims of the numerous commercially available hemp products. Hence, this review aims to compile recent advances in the science of industrial hemp, with respect to its use as value-added functional food ingredients/nutraceuticals and health benefits, while also highlighting gaps in our current knowledge and avenues of future research on this high-value multi-use plant for the global food chain.
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Parkinson’s disease (PD) is a complex, multifactorial neurodegenerative disease. The main pathological feature of PD is the loss or apoptosis of dopaminergic neurons in the substantia nigra (SN). This study aimed to investigate the protective effect of cannabidiol (CBD) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal dopamine injury by inhibiting neuroinflammation, which was one of the factors that cause neuronal apoptosis. Male SPF C57BL/6 mice were used to create a PD model by administering MPTP intraperitoneally for seven days and treated by oral administration of CBD for 14 days. Behaviorally, CBD improved cognitive dysfunction and increased the number of spontaneous locomotion in PD mice. Biochemically, CBD increased the levels of 5-HT, DA and IL-10, and decreased the contents of TNF-α, IL-1β and IL-6. Pathologically, CBD increased the expression of tyrosine hydroxylase (TH). Mechanistically, CBD up-regulated the expression of Bcl-2, down-regulated the levels of Bax and Caspase-3, and repressed the expression of NLRP3/caspase-1/IL-1β inflammasome pathway. In summary, CBD has a therapeutic effect on MPTP-induced PD mice by inhibiting the apoptosis of dopaminergic neurons and neuroinflammation. Therefore, CBD is a potential candidate for PD therapy.
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The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.
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Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.
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Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg/kg) from the 12th to the 14th postnatal days and were treated with vehicle or CBD (10 mg/kg) for 14 days in adulthood. Iron increased Caspase 9, Cytochrome c, APAF1, Caspase 3 and cleaved PARP, without affecting cleaved Caspase 8 levels. CBD reversed iron-induced effects, recovering apoptotic proteins Caspase 9, APAF1, Caspase 3 and cleaved PARP to the levels found in controls. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.
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Movement disorders such as Parkinson's disease and dyskinesia are highly debilitating conditions linked to oxidative stress and neurodegeneration. When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. Although the studies that investigate the effects of this compound on movement disorders are surprisingly few, cannabidiol emerges as a promising compound to treat and/or prevent them. Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.
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Objective: Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection. Methods: One day-old HI (carotid clamp and FiO2 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (naïve) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNFα concentration, neuroinflammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: excitotoxicity). Results: HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFα or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated. Conclusions: cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone.
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Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with a prevalence of 1–2% of all patients with epilepsy. It is characterized by multiple pharmaco-resistant seizure types, including tonic, atypical absences and tonic or atonic drop attacks, and the presence of electroencephalographic abnormalities, such as slow-spike waves and paroxysmal fast rhythms. Intellectual disability, behavioural and psychiatric disorders are common comorbidities; these disturbances have a multi-factorial pathogenesis. The selection of the most appropriate drug must be tailored to each patient and guided by the prevalent seizure type. In this paper available pharmacological options are discussed and for each pharmacological agent, current evidence of efficacy and tolerability is provided. Valproic acid represents one of the first-line options in the treatment of LGS. Anyway, other antiepileptic drugs (AEDs) may be considered and added: lamotrigine, rufinamide, topiramate, clobazam can be efficacious. The use of felbamate must be carefully evaluated because of its adverse events. Perampanel, zonisamide, levetiracetam and fenfluramine have shown to be useful in the treatment of selected patients; nevertheless, the lack of RCTs does not allow to recommend their use in a systematic way. Recently, cannabidiol has provided high evidence of efficacy against LGS seizures; however, these data must be confirmed by long-term extensive studies and by trials comparing different AEDs, one to each other.
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Anticonvulsant effects of cannabidiol (CBD), a nonpsychoactive cannabinoid, have not been investigated in the juvenile brain. We hypothesized that CBD would attenuate epileptiform activity at an age when the brain first becomes vulnerable to neurotoxicity and social/cognitive impairments. To induce seizures, kainic acid (KA) was injected either into the hippocampus (KAih) or systemically (KAip) on postnatal (P) day 20. CBD was coadministered (KA + CBDih, KA + CBDip) or injected 30 minutes postseizure onset (KA/CBDih, KA/CBDip). Hyperactivity, clonic convulsions, and electroencephalogram rhythmic oscillations were attenuated or absent after KA + CBDih and reduced after KA + CBDip. NeuN immunohistochemistry revealed neuroprotection. Augmented reactive glia number and expression were reversed in CA1 but persisted deep within the dentate hilus. Parvalbumin-positive (PV+) interneurons were reduced in both models, whereas immunolabeling was dramatically increased within ipsilateral and contralateral dendritic/neuropilar fields following KA + CBDih. Cannabinoid receptor 1 (CB1) expression was minimally affected after KAih contrasting elevations observed after KAip. Intracranial coadministration data suggest that CBD has higher efficacy in epilepsy with hippocampal focus rather than when extrahippocampal amygdala/cortical structures are triggered by systemic treatments. Inhibition of surviving PV+ and CB1+ interneurons may be facilitated by CBD implying a protective role in regulating hippocampal seizures and neurotoxicity at juvenile ages.
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Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic.
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Parkinson disease is the second-most common neurodegenerative disorder that affects 2–3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.