Table 1.

Neuroprotective effects of CBD in different neurological diseases through the activation of the A_2ARs.

In Vitro and in Vivo Models	CBD Dose	Treatments	Biological/Pharmacological Effect	Neurological Diseases	Ref.
Female SJL/J mice	5 mg/kg	Once-daily during Days 1–7 post-infection	CBD attenuated the activation of microglia downregulating the expression of VCAM-1, CCL2 and CCL5 and the proinflammatory cytokine IL-1β. Moreover, CBD improved motor deficits in the chronic phase of the disease	multiple sclerosis	[18]
Newborn C57BL6 mice	0.1–1000 µM	15 min. pre-incubation	CBD reduced acute brain damage and apoptosis. Moreover, it induced a reduction concentration of glutamate and IL-6 and decreased the expression of TNF-α, COX-2 and iNOS.	hypoxic-ischemic brain damage	[28]
Primary Rat Microglial and N13 Microglial Cells and C57Bl/6 mice	20 mg/kg	Once-daily during the first week, then 3 days/week for 2 weeks	CBD inhibited ATP-induced intracellular Ca2 + increase in cultured N13 and primary microglial cells and A2A receptors may be involved in this mechanism. In vivo, CBD reduced the gene expression of proinflammatory cytokine IL-6 and prevented cognitive impairment induced by Aβ.	Alzheimer’s disease	[84]
Female Sabra mice	5 mg/kg	Every day for 4 weeks	CBD reduced the expression of the TNF-α-receptor 1 gene in the hippocampus. Conversely, enhanced the expression of the BDNF gene. Moreover, CBD, through the indirect activation of the A2AR, improved the cognitive and motor function of the rats with Hepatic Encephalopathy.	hepatic encephalopathy	[82]

CBD, cannabidiol; VCAM-1, vascular cell adhesion molecule-1; CCL-2, chemokine ligand 2; CCL-5, chemokine ligand 5; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; A_2AR, adenosine 2A receptors; CB2, cannabinoid receptors type 2; Aβ, β-amyloid; BDNF, brain-derived neurotrophic factor.