Table 2.

CBD and neuroprotective mechanisms.

Main effect of CBD	Model	CBD Dose/concentration range	Route of administration	Species/Strain	Possible mechanism of action	References
Prevents NMDA receptor-induced excitoxicity	E17 cortical neurons culture	EC50 = 3.7 μM	In vitro	Wistar rat	Effect independent of cannabinoid receptors.	Hampson et al., 1998
↓Phosphorylated form of p38/MAP kinase, ↓Caspase 3 levels, and NFκ-b activation	β amyloid-induced neurotoxicity in PC12 cells	10 μM	In vitro	PC12 cells	Antioxidant	Esposito et al., 2006
Prevented gliosis, neuronal death and ↑ hippocampal neurogenesis	Genetic model of Alzheimer's Disease	10 mg/kg	15 days	C57BL6 mice	PPARγ	Esposito et al., 2011
↓Aβ cell viability and ↓LPS (conditioned media) induced microglia activation	β amyloid -induced neuronal toxicity in neuroblastoma cells. LPS-induced microglial-activation	10 μM	In vitro	Neuroblastoma (SH-SY5Y) cells/Microglial (BV-2) cells	Not determinated	Janefjord et al., 2014
Improved cell viability	Amyloid β -induced toxicity and tert-butyl hydroperoxide-induced oxidative stress	0.01–10 μM	15 min pre-incubation before Aβ or sAβ addition/ 24-h incubation for oxidative stress analysis	PC12 and Neuroblastoma (SH-SYS5) cells	Not determinated	Harvey et al., 2012
↓ Amyloid- β production	Amyloid β -induced neurotoxicity	100 nM	24 h	SHSY5Y (APP+) neurons	PPARγ	Scuderi et al., 2014
Reversed 3-nitropropionic acid—induced ↓ GABA contents, ↓ substance P, ↓ neuronal-specific enolase and superoxide dismutase(SOD)-2	(10 mg/kg) 3-nitropropionic acid-induced) striatal lesions	5 mg/kg	5 days, i.p.	Sprague-Dawley rats	Independent of CB1, TRPV1 and A2A receptors	Sagredo et al., 2007
↓ Levels of IL-1beta, GFAP and iNOS	Amyloid β -induced neurotoxicity	10 mg/kg	i.p.	C57BL6 mice	Not determinated	Esposito et al., 2007
Reduced dopamine depletion and ↑mRNA levels of SOD in the substantia nigra	6-hydroxydopamine toxicity	3 mg/kg	14 days, i.p.	Sprague-Dawley rats	Antioxidant	Garcia-Arencibia et al., 2007
↓Cell death	H2O2-inducedoxidative stress in Oligodendrocyte progenitor cells	1 μM	In vitro	Oligodendrocyte progenitor cells	Not determinated	Mecha et al., 2012
↓of carbonyl groups and prevents the decrease in BDNF expression	Amphetamine-induced oxidative stress	60 mg/kg	2 weeks, i.p.	Wistar rats	Not determinated	Valvassori et al., 2011
↓ NFκ-B, ↓ ICAM-1 and VACAM-1	High glucose-induced mithocondrial superoxide generation	4 μM	In vitro	Human coronary artery endothelial cells	Independent from CB1 and CB2 receptors	Rajesh et al., 2007
Prevented Aβ-induced cognitive deficits, ↓ microglia activation, ↓ IL-6 mRNA expression Inhibited NO generation and ATP-induced intracellular Ca2+ levels	Rat primary cortical cultures, N13 and BV-2 microglial cells Morris water maze	10–1,000 nM	In vitro 3 weeks: first week treated daily; second and third weeks treated 3 times/week, i.p.	Rat primary cortical cultures, N13 and BV-2 microglial cells C57BL6 mice	Some of the in vitro effects were mediated by A2A, CB1, and CB2 receptors	Martín-Moreno et al., 2011
Blocked LPS-induced STAT1 activation	LPS-induced BV-2 activation	10 μM	In vitro	BV-2 microglial cells	Not determinated	Kozela et al., 2010
↓Apoptosis; ↓Excitotoxicty and neuroinflamation	Newborn hypoxic-ischemic brain damage	0.1–1,000 μM	Ex vivo	Brain slices from C57BL6 mice	CB2 and A2A receptors	Castillo et al., 2010
Protects against the reduction in tyrosine hydroxylase activity	6-hydroxydopamine-induced toxicity in the striatum and substantia nigra	3 mg/kg	14 days, i.p.	Sprague-Dawley rats	Not determinated	Lastres-Becker et al., 2005
↑ Viable neurons and ↓ excitoxicity, oxidative stress, and inflammation	Newborn hypoxic-ischemic brain damage (HI)	1 mg/kg	30 min after HI, i.p.	Newborn pigs	CB2 and 5HT1A receptors	Pazos et al., 2013
Improve of cognition and motor activity. Restores BDNF levels	Encephalopathy (bile duct ligation)	5 mg/kg	28 days, i.p.	C57BL6 mice	5HT1A	Magen et al., 2010
Improvments od liver function, normalizes 5-HT levels, and improves brain pathology	Encephalopathy (thioacetamide)	5 mg/kg	Single dose	C57BL6 mice	5HT-dependent mechanism	Avraham et al., 2011
Faciltates autophagic flux and decrease oxidative stress	Pilocarpine-Induced Seizure	100 ng	Intracerebroventricular	Wistar rats	Induction of autophagy pathway	Hosseinzadeh et al., 2016
Suppresses the transcription proinflammatory genes	MOG35-55-specific T cell in the presence of spleen-derived antigen presenting cells	5 μM	In vitro	MOG35-55- and APCs isolated from spleens of C57BL6	Not determinated	Kozela et al., 2016
Attenuates TNF-α production and ↓ adenosine transport	murine microglia and RAW264.7 macrophages LPS-treated mice	500 nM or 1 mg/kg	In vitro	Murine microglia	A2A adenosine receptor	Carrier et al., 2006
			In vivo (1 h before LPS injection, i.p.)	RAW264.7 macrophages C57BL6 mice
Improves motor deficits in the chronic phase; ↓ microglial activation and Il-beta and TNF-α production	Viral model of multiple sclerosis	5 mg/kg	7 days, i.p	SJL/J mice	A2A adenosine receptor	Carrier et al., 2006
Normalizes synaptophyisin and caspase 3 expression	Brain damage induced by iron overload during neonatal period	Not informed	14 day, i.p.	Wistar rats	Not determinated	da Silva et al., 2014
Prevented MPP-induced toxicity and induces neurite growth	MPP-induced toxicity in PC12 cells and SH-SY5Y	1 μM	In vitro	PC12 and SH-SY5Y cells	TRKA	Santos et al., 2015
Prevents cognitive and anxiogenic effects, ↓ TNF-α and IL-6 ↑ BDNF levels	Murine model of cerebral Malaria	30 mg/kg	10 days, i.p.	C57BL6 mice	Not determinated	Campos et al., 2015

i.p., intra peritoneal; ↓, decreases; ↑, increases.