Hypoxia-Ischemia |
0.1, 1, 3 mg/kg i.p. just before and 3 h after the MCAO occlusion | ddY mice, 25–35 g | Middle cerebral artery occlusion (MCAO), 4 h | Day 3: decreased GFAP IHC (infarct including striatum) | Decreased infarct size, reduced microglia activation and apoptosis, improved neurological score, motor coordination; Infarct size reduction—not CB1 and CB2 mediated | [41] |
3, 10, and 30 mg/kg i.p., 30 min before, 3, 24, 48 h after BCCAO | Swiss mice, 35–45 days old (30–40 g) | Bilateral common carotid artery occlusion (BCCAO) using aneurysm clips, 17 min | Day 7: decreased GFAP IHC in hippocampus (HPC) | Reduced neuronal cell death and improved spatial learning | [42] |
1 mg/kg s.c. 10 min, 1, 3, 6, 12, 18, 24 h after HI | C57BL6 mice, 9–10 days old | Left common carotid artery electrocoagulation, 3 h later followed by hypoxia (10% O2) for 90 min | Day 7: decreased GFAP level (astrocyte viability) | Reduced ipsilateral hemisphere volume loss and microglia activation | [43] |
5 mg/kg i.p., 15/30 min after MCAO | Wistar rat pups, 7–9 days old | MCA occlusion, 3 h | Day 7: no effect on GFAP; Day 15: reduced GFAP (parieto-occipital cortex) | Improved neurobehavioral scores, reduced neuronal damage and microglia activation, no effect on infarct size | [44] |
1 mL of 0.1 mg/kg i.v. per ~1.7 kg weight, 15, 240 min after the HI | Piglets, 1–3 days old | Clamping both carotid arteries with vascular occluders and low oxygen (8–10%) for 20 min | 72 h post HI: CBD reversed astrocyte loss and morphology (GFAP IHC, less swallen), decreased HI-elevated S100β in the CSF | Reduced neuronal and astrocytic cell death, less TNFα(+) cells, improved brain activity and neurobehavioral performance | [45] |
100 nM, 1 and 10 μM before or immediately after the OGD, and 2 and 4 h into reperfusion | Human brain microvascular endothelial cell (HBMEC) and human astrocyte (HA) co-cultures (BBB model) | Oxygen-glucose deprivation (OGD), 4 h | 4–32 h post OGD: improved BBB permeability; 32 h post OGD: decreased cell damage (LDH release) and VCAM1 (ELISA); minor but significant decreases in IL-6 and VEGF (but not of IFNγ, IL-10, IL-1β, IL-2, CCL3, CCL4, or TNFα) | Protective effect up to 2 h into reperfusion; PPARγ and partially 5-HT1A mediated (not via CB1, CB2, TRPV1, A2A) Monocultures HBMEC: CBD increased IL-6, VEGF but decreased VCAM1; HA: CBD decreased VCAM1 | [47] |
Neurodegeneration |
5, 15, 30 mg/kg i.p., daily for 5 days post lesion | Wistar rat pups, 2 days old | Unilateral sciatic nerve transection at mid-thigh | Day 5: decreased GFAP IHC (only 15 mg/mL CBD analyzed) in ventral horn of the lumbar spinal cords | CBD 15 mg/mL rescued synaptic and sensory neurons losses, reduces microglia activation | [50] |
2.5 or 10 mg/kg i.p., daily for 7 days starting day 3 after Aβ | C57BL/6J mice, 3–5 month old | Human Aβ (1–42, 10 ng/mL) inoculation into the right dorsal hippocampus (HPC) | Day 10: decreased GFAP mRNA (in situ) and protein IHC in HPC | Decreased iNOS and IL-1β levels | [57] |
10 mg/kg i.p., for 15 days | Sprague-Dawley (SD) rats, 300–350 g | Human Aβ (1–42; 30 ng) into HPC CA1 | Day 15: Decreased GFAP, S100β in HPC homogenates and GFAP IHC in HPC CA1 | Decreased neuronal damage, neuroinflammatory signaling, increased calbindin levels in HPC CA1 and neurogenesis in the HPC DG; PPARγ mediated | [58] |
10−9–10−7 M | Cultured newborn SD rat astrocytes | Aβ (1–42) 1 µg/mL | 24 h: inhibition of S100β, NO, TNFα, IL-1β release (ELISA) and GFAP, S100β, iNOS, NF-κB (p-p50/p65) levels (WB) | PPARγ mediated | [58] |
1, 5 μM | Cultured newborn Wistar rat astrocytes | IL-1β + TNFα (both 10 ng/mL); serum free | 6 h: decreased CCL-2 (ELISA) | 7 days of CBD 5 mg/kg i.p. ameliorated TMEV EAE, decreased leukocyte infiltration, VCAM1, CCL2, CCL5, CCR2 in the PFC; reduced microglial Iba1, TNFα, IL-1β; A2A mediated | [74] |
1% CBD in propylene glycol on hind limbs daily post immunization from days 14 (EAE onset)-28 | C57BL/6 mice, 12 week old (males) | MOG35–55-induced EAE | Day 28: decreased GFAP IHC and WB in the spinal cords | Diminished clinical EAE score, T cell infiltration and demyelination in the spinal cord, decreased TNFα, IL-6, TGFβ, oxidative markers and apoptosis, increased IL-10 | [78] |
Sativex-like botanical extracts *—10 mg/kg i.p. daily days 70–80 post virus injection | SJL/J mice, 4 week old, (females) | TMEV-induced EAE | Day 80: reduced GFAP and vimentin, CSPG (CS56) IHC, brevican mRNA in spinal cord | Improved motor deficits, decreased myelin and axon damage, T cell infiltration, ICAM1, microglial Iba1, IL-1β, TNFα, IFNγ and increased Arg1 and IL10; Δ9-THC-BDS or Δ9-CBD-BDS alone mimicked Sativex-like mix in EAE via CB1 and PPARγ, respectively | [75] |
100 nM, 0.5 and 1 μM | Cultured postnatal Wistar rat astrocytes | TGFβ1 + βFGF (both 10 ng/mL) 24, 48 or 72 h; cultured 1 h in no serum DMEM before stimulation | 24 h: reduced brevican and XT-I mRNA. 48 h and 72 h: reduced neurocan (IHC and WB on supernantants) | | [75] |
3 mg/kg of Sativex-like botanical extracts * i.p., 30 min before and 2 h after injection | SD rats, 12 weeks old | Intrastriatal malonate induced Huntington-like neurodegeneration | 48 h: decreased GFAP IHC in striatum | Decreased striatal edema, microglial Iba1, iNOS and IGF1, minor prevention of cell death, reversed malonate-induced CB1 decrease; CB1 and CB2 mediated | [81] |
Other |
10, 20, 50 mg/kg 1 h before each PTZ | SD rats, 170 g | Chronic epilepsy, i.p. PTZ for 28 days | Day 28: reduced astrocyte hyperplasia (GFAP IHC in HPC CA1, CA3) | Antiepileptic, decreased neuronal loss and NMDAR1 in the HPC | [90] |
30 and 60 mg/kg i.p., days 6–28 of MK-801 injections | C57BL/6J mice, 6 weeks old | Schizophrenia model based on NMDA receptor hypofunction, 28 days of 1 mg/kg MK-801 | Day 31: Slight decrease of GFAP IHC in mPFC | Improved cognitive scores and reduced anxiety, decreased microglial Iba-1 | [98] |
30 mg/kg i.p. 2 h after each stressor | Wild type and GFAP-TK mice, 3 months old | Chronic unpredictable stress (CUS, 14 days), model of depression/anhedonia | Day 15: In WT increased HPC neurogenesis, including non-stressed controls, reversed CUS-decreased neurogenesis (NeuN, BrdU, and Dcx) | Day 14 and 15—decreased anxiety; effect ablated in GFAP-TK/ganciclovir mice; CB1 mediated, AEA increased (not 2-AG or PEA) | [107] |
50, 100, 250, 500 nM | HiB5 hippocampal progenitor cell line | BrdU expression, cell number | Increased BrdU and S phase cell cycle | CB1/CB2 mediated | [107] |
1 µM | 8-week old mouse whole brain neural/stem progenitor cells (NSPCs) | Whole brain NSPCs in vitro proliferation and differentiation into neurons or astrocytes | Day 2: Increase in nestin mRNA (B27 supplemented medium) and cell viability, no effect on GFAP mRNA | No effect on nestin in complete medium | [108] |
10 µM 1–3 days | Human glioblastoma multiforme cells (U87MG, MZC) | Cell death and viability, colony formation following CBD alone and in combination with BCNU, TMZ, and DOXO | Days 1–3: potentiates cytotoxicity of BCNU, TMZ, and DOXO chemotherapeutics | TRPV2-dependent Ca2+ influx | [121] |
10 µM 1–3 days | Normal human astrocytes (NHA) | Cell death and viability following CBD alone and in combination with BCNU, TMZ, and DOXO | No effect on cell viability alone or in combination with BCNU, TMZ, and DOXO chemotherapeutics | | [121] |