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The endocannabinoid system (ECS) is a complex cell-signaling system that modulates various physiological and cognitive processes, such as pain, mood, memory, sleep, and appetite[1]. It plays a crucial role in the protection of neurons from damage caused by trauma, ischemia, neuroinflammation, or neurodegeneration [1,2]. The ECS’s neuroprotective mechanisms involve direct activation of cannabinoid receptors and indirect modulation of the ECS by affecting the synthesis, degradation, or transport of endogenous cannabinoids [1,2].
The ECS consists of cannabinoid receptors, CB1 and CB2, which are distributed in the central nervous system (CNS) and peripheral nervous system (PNS)[1]. CB1 receptors are predominantly found in neurons, while CB2 receptors are mainly found in astrocytes, microglia, and immune cells [9,10]. These receptors are activated by endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), as well as phytocannabinoids and synthetic cannabinoids [1,2].
Several neuroprotective mechanisms are mediated directly by cannabinoid receptors, while others involve indirect modulation of the ECS by affecting the synthesis, degradation, or transport of endogenous cannabinoids [1,2]. For example, fatty acid amide hydrolase (FAAH) inhibitors can increase AEA levels by preventing its breakdown, enhancing its neuroprotective effects [3]. Similarly, monoacylglycerol lipase (MAGL) inhibitors can elevate 2-AG levels by inhibiting its hydrolysis, thereby conferring neuroprotection [4].
Additionally, some compounds interact with non-cannabinoid receptors involved in ECS regulation, such as transient receptor potential vanilloid 1 (TRPV1) channels, which modulate CB1 activity when co-expressed [2]. Moreover, some compounds may influence the ECS by altering the expression or signaling of neurotransmitters or hormones interacting with cannabinoid receptors, such as serotonin, steroids, cytokines, dopamine, glutamate, and leptin [2].
A 2022 in-vivo study showed that acute administration of THC to mice subjected to traumatic brain injuries (TBI) led to significant recovery from the TBI [5]. The cannabinoid type I and II receptors (CB1 and CB2) are potent regulators of glutamate release, exhibit anti-inflammatory properties, and facilitate antioxidant effects [6]. Supporting THC’s protective benefits, TBI patients with THC in their blood have been found to be more likely to survive their injury than those without [7].
Two other recent in-vivo studies found that CBD may have neuroprotective effects beyond those previously studied in the ECS. The first study showed that CBD administration was able to prevent acute hepatic toxicity and seizures induced by cocaine in mice, while the second study found that CBD was able to attenuate neuroinflammation, seizures and EEG abnormalities in a mouse model of Angelman syndrome, suggesting that CBD may have potential therapeutic applications for neurodevelopmental disorders [8,9].
There are several endogenous neuroprotective compounds that have been shown to indirectly interact with the ECS, either by modulating the levels or actions of endogenous cannabinoids, or by affecting other receptors or systems related to the ECS [1,2]. These compounds may offer novel therapeutic opportunities for the prevention or treatment of various neurological disorders involving neuronal damage.
In summary, several endogenous neuroprotective compounds indirectly interact with the ECS, either by modulating endogenous cannabinoid levels or actions or by affecting other receptors or systems related to the ECS [1,2]. These compounds may offer novel therapeutic opportunities for the prevention or treatment of various neurological disorders involving neuronal damage.
The table below presents the CB1 and CB2 receptor status and the implications for neuroprotection in some of the most important cell types in the CNS.
| Cell Types | CB1 Expression Level | CB2 Expression Level | Significance |
| Neurons | High | Low | Excitatory and inhibitory neurons are primary targets of endocannabinoid signaling, with CB1 receptors playing a major role in synaptic plasticity and neurotransmitter release [10]. |
| Astrocytes | Low-Moderate | High | Astrocytes express both CB1 and CB2 receptors, with CB2 receptors playing a key role in regulating inflammation and neuroprotection through the ECS [11]. |
| Microglia | Low | High | Microglia express CB2 receptors at high levels and and play a role in immune regulation and neuroinflammation through the ECS. [12] |
| Oligo-dendrocytes | Low | Low-Moderate | Oligodendrocytes express CB1 and CB2 receptors at low to moderate levels and may play a role in myelin formation and neuroprotection through the ECS [13] |
The research and understanding of the endocannabinoid system have led to new insights into the neuroprotective mechanisms associated with this complex signaling system. The role of CB1 and CB2 receptors in neurons, astrocytes, microglia, and oligodendrocytes in the CNS, as well as the modulation of endogenous cannabinoid levels and interactions with other receptors or systems, provide a solid foundation for the development of targeted therapies aimed at preventing and treating various neurological disorders involving neuronal damage.
Future research may focus on further characterizing the ECS, identifying additional endogenous or exogenous modulators, and understanding the molecular and cellular mechanisms underlying the ECS’s neuroprotective effects. This research could lead to the development of novel therapeutic approaches that harness the endocannabinoid system’s potential to promote neuroprotection and recovery from neuronal damage.
Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal
- Xin, Q., Xu, F., Taylor, D.H. et al. The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders. Acta Pharmacol Sin 41, 1507–1518 (2020). https://doi.org/10.1038/s41401-020-00530-2
- Busquets-Garcia, A., Bains, J. & Marsicano, G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacol. 43, 4–20 (2018). https://doi.org/10.1038/npp.2017.206
- Papa A, Pasquini S, Galvani F, et al. Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions. Eur J Med Chem. 2023;246:114952. doi:10.1016/j.ejmech.2022.114952
- Choi SH, Arai AL, Mou Y, et al. Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke [published correction appears in Stroke. 2018 Sep;49(9):e294]. Stroke. 2018;49(3):718-726. doi:10.1161/STROKEAHA.117.019664z§z§
- Song S, Kong X, Wang B, Sanchez-Ramos J. Recovery from Traumatic Brain Injury Following Treatment with Δ9-Tetrahydrocannabinol Is Associated with Increased Expression of Granulocyte-Colony Stimulating Factor and Other Neurotrophic Factors. Cannabis Cannabinoid Res. 2022;7(4):415-423xx
- Hayakawa K, Mishima K, Nozako M, et al. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem. 2007;102(5):1488-1496. doi:10.1111/j.1471-4159.2007.04565.x
- Nguyen BM, Kim D, Bricker S, et al. Effect of marijuana use on outcomes in traumatic brain injury. Am Surg. 2014;80(10):979-983.
- Vilela LR, Gomides LF, David BA, et al. Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine. Mediators Inflamm. 2015;2015:523418. doi:10.1155/2015/523418
- Nakamura Y, Okamoto N, Kurata T, et al. Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice. Neuropharmacology. 2021;181:108382. doi:10.1016/j.neuropharm.2020.108382
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- Molina-Holgado E, Vela JM, Arévalo-Martín A, et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci. 2002;22(22):9742-9753. Doi:10.1523/JNEUROSCI.22-22-09742.2002