The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects
Abstract
:1. Introduction
2. Phytochemicals in Medicinal Cannabis
3. The Endocannabinoid System and Neuroinflammation
4. Anti-Neuroinflammatory Activity of Phytochemicals in C. sativa
4.1. CBD
4.2. THC
4.3. CBG
Compound | Model | Concentration/Dose | Indicated Neurodegenerative Diseases | Outcome | References |
---|---|---|---|---|---|
CBD | in vitro glutamate neuronal toxicity model | N/A | N/A | CBD was shown to be more protective than either α-tocopherol or vitamin C and comparable to butylated hydroxytoluene (BHT) | [108,109] |
THC | in vivo in hemiparkinsonian rats | N/A | PD | neuroprotective effect | [110] |
CBD | in vivo in hemiparkinsonian rats | 3 mg/kg | PD | exhibited a potent neuroprotective effect in this rat model | [110] |
CBD | N/A | <1 μM | N/A | inhibit activated microglial cell migration by antagonising the abnormal cannabidiol (Abn-CBD)-sensitive receptor | [111] |
CBD | in vitro PC12 cells | N/A | AD | neuroprotective against the neuronal damage induced by the β-amyloid peptide (Aβ); inhibits Aβ-induced neurotoxicity | [112] |
CBD | in vivo mouse model | N/A | AD | attenuated the expression of several glial pro-inflammatory proteins, including glial fibrillary acidic protein, inducible nitric oxide synthase (iNOS), and interleukin 1β (IL-1β), which are major contributors to the propagation of neuroinflammation and oxidative stress | [113] |
CBD | in vivo mouse model | 100–200 mg/kg | Dravet syndrome | it has beneficial effects on seizures and social deficits | [114] |
CBD | in vivo mouse model | 10 mg/kg twice daily | Schizophrenia | improves social and cognitive dysfunctions | [115] |
CBDV | clinical trial | Single oral dose | ASD | it modulates glutamatergic but not γ-aminobutyric acid (GABA) neurotransmission in adult male patients, although the biological response may differ between autistic individuals | [116] |
THCV | in vivo mouse model | <3 mg/kg | PD | alleviates motor inhibition in 6-OHDA-lesioned rodents by blocking CB1 receptors at low doses | [117] |
THC | N/A | N/A | PD | it reduced levodopa-induced dyskinesia | [118] |
CBN | in vitro C6 glioma cells | 0.3–30,000 nM EC50: 700 nM | N/A | it inhibited NO production and iNOS expression | [113] |
CBN | N/A | N/A | MS | it may antagonise the 2-AG-induced recruitment of microglial cells and produces minimal palliative effect | [111] |
THC | in vitro BV-2 murine microglial cell line | 10 μM | N/A | it decreases the production and release of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and interferon (IFN)β, from LPS-activated microglial cells | [94] |
CBG | in vitro murine microglial cell line | 25 μM | MS | it inhibited the microglia-driven inflammatory response, protected neurons from toxic insults in vitro, and restored motor function impairment by inhibiting the synthesis of IL-1β, IL-6, TNF-α, the chemokine, MIP-1α, and prostaglandin E2 (PGE2) | [119,120] |
CBG | in vitro NSC-34 motor neurons | 7.5 µM | N/A | CBG pre-treatment REDUCED IL-1β, TNF-α, IFN-γ, and PPARγ protein levels and reduced nitrotyrosine, SOD1, and iNOS protein levels and restored Nrf-2 levels | [106] |
CBG | in vivo and in vitro | N/A | PD | it shows a neuroprotective effect against inflammation-driven neuronal damage, acting through the activation of the canonic binding site in PPARγ receptors | [121] |
CBG | in vivo and in vitro neuroblastoma Neuro-2a (N2a) | 2 g/6.319 mM | HD | it improved motor deficits, reactive astrogliosis, and microglial activation, inhibiting the upregulation of pro-inflammatory markers and improving antioxidant defences in the brain | [122] |
CBDA | in vitro Neuro-2a (N2a) cells | 25 μM | HD | CBDA shows potent neuroprotective activity by activating PPARγ with higher potency than their decarboxylated products | [123] |
CBDA | in vivo | 10 and 30 mg/kg | Dravet syndrome | it has an anticonvulsant effect against pentylenetetrazol-induced seizures and hyperthermia-induced seizures | [124] |
CBDV | in vivo mouse model | CBDV | Rett syndrome (RTT), a rare neurological disorder affecting predominantly females | it improves behavioural and functional deficits | [125,126,127,128] |
CBC | in vitro | 1 μM | N/A | CBC exerts potential actions on brain health through effects on adult neural stem cells using whole brain-derived neural stem progenitor cells (NSPCs) | [129] |
THC | in vitro | 10 μM | N/A | THC reduces IL-1β, IL-6, and TNFα production in LPS-stimulated rat microglial cells | [130] |
THC | in vitro | 0–15 μM | AD | it inhibits the enzyme acetylcholinesterase (AChE) and prevents AChE-induced amyloid β-peptide (Aβ) aggregation, which is considered the key pathological marker of Alzheimer’s disease | [101] |
THC | in vivo R6/1 mouse model | 10 mg/kg | HD | it inhibits acetylcholine esterase (AchE)-induced aggregation of Aβ and attenuates the motor coordination deficits of R6/1 mice | [100] |
THCA | in vitro N2a cells | 10 μM IC50 of 0.47 μM | HD | it has neuroprotective activity by activating PPARγ transcriptional activity | [123] |
4.4. Terpenes
4.5. Flavonoids
5. Entourage Effects among the Phytochemicals in C. sativa
5.1. The Preclinical and Clinical Evidence
5.2. The Entourage Effects in the Context of Neuroinflammation
5.3. The Mechanisms That Underpin the Entourage Effects
6. Conclusions and Future Directions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Al-Khazaleh, A.K.; Zhou, X.; Bhuyan, D.J.; Münch, G.W.; Al-Dalabeeh, E.A.; Jaye, K.; Chang, D. The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects. Molecules 2024, 29, 410. https://doi.org/10.3390/molecules29020410
Al-Khazaleh AK, Zhou X, Bhuyan DJ, Münch GW, Al-Dalabeeh EA, Jaye K, Chang D. The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects. Molecules. 2024; 29(2):410. https://doi.org/10.3390/molecules29020410
Chicago/Turabian StyleAl-Khazaleh, Ahmad K., Xian Zhou, Deep Jyoti Bhuyan, Gerald W. Münch, Elaf Adel Al-Dalabeeh, Kayla Jaye, and Dennis Chang. 2024. "The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects" Molecules 29, no. 2: 410. https://doi.org/10.3390/molecules29020410