Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid
Abstract
:1. Astrocytes
2. Astrocytes as Potential Therapeutic Target. Role of Cannabinoid System
3. Neurodegeneration
3.1. Stroke, Hypoxia-Ischemia
3.2. Sciatic Nerve Transection
4. Chronic Neurodegenerative Diseases
4.1. Alzheimer’s Disease
4.2. Autoimmune Diseases
4.3. Huntington’s Disease
5. Epilepsy
6. Neuropsychiatric Disorders
7. Neurogenesis
8. Receptors Involved
9. Remarks
9.1. Serum-Free Sensitization to CBD Toxicity
9.2. Astrocyte Activity Markers
9.3. Astrocyte Heterogeneity
9.4. The Interaction of CBD with Other CNS Cells
10. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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CBD Doses/Times | Animals or Cells | Procedure | Astrocyte Activity Measures | Other CBD Activities | Refs. |
---|---|---|---|---|---|
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] |
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Kozela, E.; Juknat, A.; Vogel, Z. Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid. Int. J. Mol. Sci. 2017, 18, 1669. https://doi.org/10.3390/ijms18081669
Kozela E, Juknat A, Vogel Z. Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid. International Journal of Molecular Sciences. 2017; 18(8):1669. https://doi.org/10.3390/ijms18081669
Chicago/Turabian StyleKozela, Ewa, Ana Juknat, and Zvi Vogel. 2017. "Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid" International Journal of Molecular Sciences 18, no. 8: 1669. https://doi.org/10.3390/ijms18081669