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2013;75:323-33. but can be related to a reduction in glutamate excitotoxicity and oxidative stress,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. neuroinflammation decrease,9191. Santiago AN, Mori MA, Guimaraes FS, Milani H, Weffort de Oliveira RM.

Neurotox Res. 2019;35:463-74. anti-apoptotic action,9292. da Silva VK, de Freitas BS, Garcia RC, Monteiro RT, Hallak JE, Zuardi AW, et al. Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload. Transl Psychiatry. 2018;8:176. or modulation/polarization of glial cells. 9393. Friedman LK, Wongvravit JP.

J Neuropathol Exp Neurol. 2018;77:904-19. In spite of the involvement of CB2 receptors in the neuroprotective effect of CBD in a model of hypoxic-ischemic in newborn mice,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage.

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2019;146:1-11. the possibility of its direct action at these receptors remains controversial. 8686. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.

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2001;134:845-52.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD also interacts with several other targets. 6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.

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2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. One of them is a family of ionotropic receptors permeable to monovalent cations and calcium named transient receptor potential vanilloid (TRPV). 8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.

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2008;153:199-215.,9595. Harteneck C, Plant TD, Schultz G. From worm to man: three subfamilies of TRP channels. Trends Neurosci. 2000;23:159-66. 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).

Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. On the other hand, at high concentrations (micromolar scale), CBD activates TRPV2, TRPV3, and TRPV4 receptors and peroxisome proliferator-activated receptor-γ (PPAR-γ).

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Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD is also an antagonist of the orphan receptor GPR559696.

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The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092-101. and it may also increase intracellular calcium in physiological conditions but decrease it under high neuronal excitability conditions. 6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.

2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. Several in vitro experiments have demonstrated promising 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.

9797. Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RH, et al. The neuroprotection of cannabidiol against MPP(+)-induced toxicity in PC12 cells involves trk, A receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease. Toxicol In Vitro. 2015;30:231-40. CBD also protected SH-SY5Y cells against LPS- and β-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.9898.

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Cannabinoid effects on beta amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell Mol Neurobiol. 2014;34:31-42. 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.