Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Endocanabinoid System
2.1. Endocannabinoids
2.2. Endocanabinoid Receptors
2.3. Neuroprotection Roles
3. Cannabinoids and Alzheimer’s Disease
4. Cannabinoids and Parkinson’s Disease
5. Cannabinoids and Huntington’s Disease
6. Cannabinoids and Multiple Sclerosis
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
2-AG | 2-Arachidonoylglycerol |
3-NP | 3-Nitropropionic acid |
5-HT1A | 5-Hydroxytryptamine |
AchE | Acetylcholinesterase |
ACPA | Arachidonyl-cyclopropyl amide |
AD | Alzheimer’s Disease |
AEA | Anandamide |
ALS | Amyotrophic lateral sclerosis |
APP | Amyloid precursor protein |
BBB | Blood–Brain Barrier |
BLA | Basolateral amygdala |
CA1 | Dorsal hippocampus |
CB1R | Cannabinoid-receptors type 1 |
CB2R | Cannabinoid-receptors type 2 |
CBD | Cannabidiol |
CBD-DMH | Cannabidiol dimethylheptyl |
CBG | Cannabigerol |
CBR | Cannabinoid receptor |
CIDP | Chronic inflammatory demyelinating polyneuropathy |
CNS | Central nervous system |
COX | Cyclooxygenase |
DMT | Disease modifying therapy |
EAE | Experimental autoimmune encephalomyelitis |
ECB | Endocannabinoid |
ECS | Endocannabinoid system |
FAAH | Fatty acid amide hydrolase |
GABA | Gamma-aminobutyric acid |
GBS | Guillain–Barré syndrome |
GPRC | G-Coupled protein receptor |
GSK-3β | Glycogen synthase kinase-3β |
HD | Huntington’s Disease |
HTT | Huntingtin |
IL | Interleukin |
i.p. | Intraperitoneal |
L-DOPA | Levodopa |
MAGL | Monoacylglycerol lipase |
MAPK | Mitogen-activated protein kinases |
MCA | Middle cerebral artery |
MHC | Major histocompatibility complex |
mHTT | Mutant huntingtin |
MOG | Myelin oligodendrocyte glycoprotein |
MPTP | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
MS | Multiple Sclerosis |
MSN | Medium spiny neurons |
NAc | Nucleus accumbens |
NAPE-PLD | N-arachidonoyl phosphatidylethanolamine-specific phospholipase D |
NF-kB | Nuclear factor-kB |
NMDA | N-Methyl-D-aspartic acid |
NTF | Neurofibrillary tangles |
OKA | Okadaic acid |
PD | Parkinson’s Disease |
PEA | Palmithoylethanolamide |
PFC | Prefrontal cortex |
PG | Prostaglandin |
PKA | Protein kinase A |
PPMS | Primary-progressive MS |
PRMS | Progressive-relapsing MS |
ROS | Reactive oxygen species |
RRMS | Relapsing-remitting MS |
SPMS | Secondary-progressive MS |
TMEV | Theiler’s murine encephalomyelitis virus |
TNF-α | Tumor necrosis factor-α |
TRPV | Transient receptor potential vanilloid |
VTA | Ventral tegmental area |
Δ9-THC | Δ9-Tetrahydrocannabinol |
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Mechanisms of AD Pathogenesis | Implications of the ECS in AD | Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of AD | |||
---|---|---|---|---|---|
Target Components | Physiological Function | Disease Model and Species | Compound | BIOLOGICAL EFFECT | |
β-amyloid (Aβ) peptides →neurodegenerative cascade → neuronal cell death [35,75,79,80] | CB1R activation | hyperpolarization of the neuronal membrane modulating of neurotransmitter and cytokine release [79] | Rats intra-CA1 microinjection i.p. intra-NAc intra-mPFC | ACPA (agonist of CB1R) | cognitive impairments [52,81] |
[35,75,79,80] | ↑ CB1R density | neuroprotective and anti-inflammatory response [79] | Rats intra-CA1 microinjection intra-NAc intra-BLA | AM251 (antagonist of CB1R) | enhanced memory and learning processes [52,81] |
Rat hippocampus | CBD and Δ9-THC | ↑ synthesis of tryptophan → improvement of the disease [82] | |||
In vitro Methods Molecular docking | Cannabinoids (CBD, CBD-DMH) | ↓ of oxidative stress ↓ of TNF-α synergistic effect with AchE inhibitors →
| |||
proteolytic cleavage of β-APP → formation of Aβ1-42 monomers → activation of astrocytes and microglia → release of inflammatory cytokines, kinases and nitric oxide → phosphorylation of tau proteins [84] | Endocannabinoids (2-AG) CB1R/CB2R activation | synthesized by microglia and astrocytes → suppress cytokine synthesis via CB1/CB2 receptors | Primary hippocampal neuron cell cultures from rat embryos | MAGL inhibitors (URB 602 andJZL 184) | ↑ endogenous levels of 2-AG → ↓ of TUNEL-positive neurons
|
(added space) GSK-3β promotes tau proteinhyperphosphorylation → formation of NFT → impairing the axonal transport → neuronal atrophy [75] | neuroprotective effects → targeting this pathway with key roles in AD pathogenesis | PC12 cells treated with Aβ | CBD AEA WIN 55,212–2 | attenuation of tau hyperphosphorylation by inhibiting Gsk-3β [75] | |
increased COX-2 levels → involvement in neuroinflammation [86] | 2-AG is substrate for COX-2 2-AG suppress elevation of hippocampal COX-2 expression | MAGL inhibitor (URB602) and nonselective MAGL inhibitor (ATFMK) | ↑ 2-AG levels → suppresses the expression of COX-2 action mediated by CB1R [86] | ||
tau pathology [87] | CB2R activation | role in memory processing its activation → vital for cognitive processes a depletion or disruption of these receptors in rodents →induces long-lasting memory deficits | Rats | AM630 (CB2R antagonist) | negative effects such as impaired memory [87] |
Rats → impaired memory by administration of okadaic acid | JWH-133 (CB2R agonist) | reduced spatial memory impairment reduced neuroinflammation and neurodegeneration [87] | |||
formation of Aβ peptide aggregates in the brain [88] PPAR- γ involvment in disease management [89] | CB2R activation | involved in controlling Inflammation | Beta-amyloid challenged astrocytes | CBD ± PPAR- γ antagonist (MK886 or GW9662) | interacts with the PPAR-γ receptor →
|
Aβ peptide-induced neurotoxicity, oxidative stress and inflammatory status | CB2R activation | enhances immune system response andautophagy pathway | Analyses of transcriptome of APP/PS1 mice hypocampus | CBD, chronic i.p. injection (30 days) | improvement of the neuroinflammation and oxidative stress level [90] |
neuroinflammatory mechanism | CB2R activation | ameliorate the neuroinflammation and cognitive impairments of AD | APP/PS1 mice | JWH015 | improvement of novel object recognition regulation in microglia-mediated neuroinflammation [92] |
evidence that associates neutrophil-derived myeloperoxidase (MPO) in the pathogenesis of AD | CB1R activation | Murine model (male mice) induced with focal cerebral ischaemia | Δ9-THC and SR141716 (CB1-R antagonist)/ AM630 (CB2R antagonist) | CB1R antagonist inhibited the neuroprotective effect of Δ9-THC CB2R antagonist had no effect
| |
mechanism of inhibition of myeloperoxidase independent of the cannabinoid receptor | CBD | (added space) the neuroprotective effect CBD was not inhibited by both CB1R and CB2R antagonist → effects, independent of cannabinoid receptors
| |||
β-amyloid (Aβ) plaques cause injuries in the pulvinar nucleus → disruption of thalamo-cortical circuits including disturbances in visual attention [93] | CB1R NAPE-PLD FAAH located in the thalamus - pulvinar nucleus (lateral, medial and inferior) - dorsal lateral geniculate nucleus | physiological connections withprefrontal cortex and amygdala [94,95,96,97] | Coronal brain sections from Vervet monkey | (added space) | |
Patients with AD | Δ9-THC CBD |
Mechanisms of PD Pathogenesis | Implications of the ECS in PD | Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of PD | |||
---|---|---|---|---|---|
Target Components | Physiological Function | Disease Model and Species | Compound | Biological Effect | |
↓ tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta down-regulation of CB2Rs in the substantia nigra | CB2R | neuroprotective effect are involved in neuroinflammation [25,105] | MPTP-induced mouse model of Parkinson’s disease | WIN 55,212 –2JW015 (CB2 receptor agonist) | protects neuron loss reduces MPTP-induced microglial activation reverses MPTP-associated motor deficits [37] reduce inflammation in the brain of MPTP-treated mice [25] |
side effects of current anti-parkinsonian therapies, especially L(3,4) dihydroxyphenylalamine L-DOPA-induced dyskinesia [108] | CB1R | modulation of neurotransmission and contribution to synaptic plasticity [108] | WIN 55,212–2 HU210 | protected nigrostriatal dopamine neurons reduced microglia activation [109] | |
↓ dopaminergic neurons in the substantia nigra compacta and a significant reduction of striatal dopamine [104] | CB2R | CB2R-deficient mice showed an exacerbation of PD pathology [25] | AM1241 (selective CB2R agonist) | regenerated dopaminergic neurons reversed the decreased CB2R level in the PD mouse brain [104] | |
currently therapy for PD is symptomatic whose efficacy is limited due to side effects | CB1R | neuroprotective properties against excitotoxicity and oxidative stress neuroinflammation, which are also associated with PD [104] | Clinical study on PD patients | CBD | change in patients’ lives possible neuroprotective effects assessed [106] |
Mechanisms of HD Pathogenesis | Implications of the ECS in HD | Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of HD | |||
---|---|---|---|---|---|
Target Components | Physiological Function | Disease Model and Species | Compound/Intervention | Biological Effect | |
mHTT - direct repressive effect on CB1R gene transcription→ Loss of CB1R binding in the striatum→ Reduction of CB1R [130,133] | CB1 Ractivation | CB1R are necessary to counteract neuronal degeneration [133] Activation of CB1R pathway is associated with a protective effect [135] CB1R activation protects neurons from NMDA-induced excitotoxicity and inhibits presynaptic release of glutamate [60] | R6/1 transgenic HD mouse model | WIN 55,212-2 | Antihyperkinetic activity prevention of motor impairment [147] |
Environment enrichment | Upregulation of CB1R binding → behavioral improvement [134] | ||||
R6/2 mouse model of HD | Δ9-THC | ↓ of motor coordination deficits improvement of motor and exploratory behavior ↓ of striatal atrophy and HTT aggregate accumulation [136] | |||
3NP animal model of HD | CBD | Reversibility or attenuation of alterations induced by 3NP [146] | |||
CBG | Prevention of striatal neuron death Improvement of motor deficits Reduction of inflammatory markers [153] | ||||
R6/2 model of HD | GAT211 GAT228 GAT229 (positive allosteric modulators) | Improvement measures of health GAT211 and GAT229 reduced psychoactivity, without tolerance or dependence [137,138,139] | |||
N171-82Q transgenic model | CB1R gene inactivation | Earlier and exacerbated motor alternations Increased striatal aggregation frequency [136] | |||
3NP animal model of HD | CB1R are necessary to counteract neuronal degeneration [133] | ||||
Rat model of HDExcitotoxicity was increased through striatal injection of quinolinic acid | WIN 55,212-2 CBD | Decreased bothglutamate levels and the effect of quinolinic acid on corticostriatal local field potential recordings [148] | |||
Cell culture model of HD with mHTT expressive cells | CBD Δ8-THC Δ9-THC | 51–84% protection against HTT-induced cell death [155] Remark: Effects might be independent of CB1R and due to antioxidant mechanisms | |||
Microglial CB2R → induced in HD patients and animal models CB2R ablation exacerbates microglial activation and accelerates appearance of symptoms [140] | CB2R | CB2R activation → neuroprotective effect in HD models → control of deleterious microglial activity [140] | Quinolinic-acid lesioned mice model of HD | HU-308 | Reduction of neuronal damage in the striatum by attenuating glial activation [140] |
Malonate-lesion rat model of HD | Accelerated progression of the HD phenotype Increased glial activation Higher sensitivity to striatal neurodegeneration induced by excitotoxic processes [140] | ||||
R6/2 mice model | CB2R ablation | Faster progression of the disease phenotype Increased glial activation Higher sensitivity to striatal neurodegeneration induced by excitotoxic processes [140] | |||
CB1R/CB2R | Human studies-patients with HD | Nabilone Sativex® | Improvements in chorea Improvements in the neuropsychiatric index Trend for improvements in the Unified HD Rating scale motor score, dystonia subscore and behavior score [151] | ||
Human studies-patients with early-onset HD | Nabilone Sativex® Dronabinol | Improvement of dystonia Quality of life improvement Behavior improvement [152] | |||
TRPV1 | HD rat model with bilateral striatal injection of 3NP | AM404 (ECB reuptake inhibitor) | Reduction of hyperkinetic activity and restoration of neurochemical alterations [1,145] |
Mechanisms of MS Pathogenesis | The Endocannabinoid System and Its Implications in MS | Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of MS | |||
---|---|---|---|---|---|
Target Components | Physiological Function | Disease Model and Species | Compound | Biological Effect | |
spasticity → the mainly observed symptom in MS is associated with spasms, pain and sleep disturbance [176,177] | CB1R and CB2R | CB1R inhibits synaptic transmission → main target for control of spasticity [204] | chronic relapsing EAE | Δ9-THC methanandamide (analogue of AEA) (CB1R agonists) WIN 55,212-2 (CB1R/CB2R agonist) JWH-133 (CB2-R agonist) | amelioration of some motor symptoms such as limb spasticity, tremor and paralysis [203] |
inflamamation→ recruitment of leukocytes from the blood into the CNS adhesion to endothelial cells (added space) cerebrospinal fluid: increased glutamate level, differential expression of glutamate receptors [232] increased glutamate level → neurodegeneration due to excitotoxicity [210,216] | CB1R and CB2R | CB2R have immunomodulatory properties [209] | EAE induced C57BL/6 mice immunized with MOG35–55 + pertussis toxin | WIN 55,212-2 SR 141716A (CB1R antagonist) SR144528 (CB2R antagonist) | CB1R antagonist → no influence on the protective effect → key role in the protective effect of WIN55212-2 [212] stimulation → attenuated EAE progression potential target to inhibit leukocyte trafficking in EAE [209] |
CB1R | activation of cannabinoid receptors inhibits the release of glutamate presynaptically [217] | Rat hippocampal neurons culture | AEA Memantine Δ9-THC | (added space) antiglutamatergic effects by ↓ of Mg2+ concentration →↓ excitation level in the entire network of neurons in the culture glutamatergic excitatory postsynaptic currents elicited by direct stimulation of the presynaptic neuron [217] | |
EAE induced C57BL/6 mice—i.p. administration for 3 consecutive days | CBD | (added space) Low dose of CBD → ↓ inflammation → axonal damage ↓ spinal activation of glia inhibition of T-cell migration in the spinal cord [220] High dose of CBD → ↓microglial activity↓ ↓cell infiltration and demyelination ↓axonal damage ↓levels of IL-6 [221] | |||
CB1R and CB2R | involvement in treating of neurodegenerative diseases driven by chronic neuro-inflammation | EAE-induced C57BL/6 mice immunized with MOG35–55 + pertussis toxin | Δ9-THC + CBD | Δ9-THC + CBD→attenuates the development of EAE [157] | |
CB1R | immunosuppressive effects on astrocytes | In vitro method TMEV-infected astrocytes | AEA | dose-dependent potentiating of IL-6 [219] inhibition of astrocytes activation →the production of IL-6 [231] inhibition IL-1β, IL-6, IL-12 and IL-23 release in myeloid dendritic cells inhibition of microglial activation [161] | |
Mouse model TMEV-induced demyelinating disease | PEA | ↓ expression of IL-1, TNF-α↓ microglial activation in the spinal cord of mice [228] | |||
UCM707 WIN 55,212-2 JWH-015 ACEA | ↓ microglial activation inhibition of MHC class II antigen expression ↓ of spinal cord infiltrating CD4T cells– ↓ the production of IL-1β, IL-6 and TNF-α [229,230] |
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Vasincu, A.; Rusu, R.-N.; Ababei, D.-C.; Larion, M.; Bild, W.; Stanciu, G.D.; Solcan, C.; Bild, V. Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty. Biology 2022, 11, 440. https://doi.org/10.3390/biology11030440
Vasincu A, Rusu R-N, Ababei D-C, Larion M, Bild W, Stanciu GD, Solcan C, Bild V. Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty. Biology. 2022; 11(3):440. https://doi.org/10.3390/biology11030440
Chicago/Turabian StyleVasincu, Alexandru, Răzvan-Nicolae Rusu, Daniela-Carmen Ababei, Mădălina Larion, Walther Bild, Gabriela Dumitrița Stanciu, Carmen Solcan, and Veronica Bild. 2022. "Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty" Biology 11, no. 3: 440. https://doi.org/10.3390/biology11030440