Cannabidiol Targets Mitochondria to Regulate Intracellular Ca<sup>2+</sup>Levels

Ryan, Duncan; Drysdale, Alison J.; Lafourcade, Carlos; Pertwee, Roger G.; Platt, Bettina

doi:10.1523/jneurosci.4212-08.2009

Cited by 223 publications

(196 citation statements)

References 67 publications

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“…In the present study, administration of KA to rats to induce epilepsy caused persistent activation of glutamate AMPA/kainate receptors triggering a sustained neuronal influx of Na + and Ca 2+ , causing prolonged depolarization and prolonged Ca 2+ influx into the cytoplasm. However, previous studies suggest that CBD exerts an activity‐dependent biphasic control over Ca 2+ levels (Ryan et al, 2009); hence, it is likely that in our experiments, CBD treatment of epileptic rats exerted a neuroprotective function by preventing intracellular Ca 2+ overloading during hyperactivity, thus halting oxidative stress. This would trigger mitochondrial oxidation (Hajnoczky et al, 2006), contributing to the degenerative process of neurons (Liang et al, 2000; Patel, 2004; Waldbaum et al, 2010).…”

Section: Discussionmentioning

confidence: 71%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

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Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.

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Section: Discussionmentioning

confidence: 71%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

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“…Under normal physiological Ca 2+ conditions, CBD slightly increases intracellular Ca 2+ , whereas CBD reduces intracellular Ca 2+ under high-excitability conditions. These changes were blocked by the pretreatment with an antagonist of the mitochondrial Na + / Ca 2+ exchanger, suggesting a mitochondrial site of action [111]. CBD also produces biphasic changes in intracellular calcium levels via antagonism of the mitochondrial voltagedependent anion channel 1 [112].…”

Section: Cbdmentioning

confidence: 98%

“…CBD exerts dynamic control over intracellular calcium stores through multiple, activity-dependent pathways [110,111]. CBD induces a bidirectional change in intracellular calcium levels that depends on cellular excitability.…”

Section: Cbdmentioning

confidence: 99%

Cannabinoids and Epilepsy

et al. 2015

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Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabisbased antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro-and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

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“…VDAC1 plays a key role in controlling calcium flux into mitochondria, and intracellular calcium can increase VDAC1 expression and oligomerization, which is associated with increased apoptosis; in particular, it is thought that VDAC1 selectively transfers apoptotic calcium signals to the mitochondrion [226,227]. Two other groups have also shown that CBD could apparently control intracellular calcium flux in a mitochondrially dependent way, which, overall, suggests that CBD, via a VDAC1-related mechanism, could play an important role in controlling calcium flux in neurodegeneration [228,229].…”

Section: Cbd Ion Channels Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

447

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Cannabidiol Targets Mitochondria to Regulate Intracellular Ca²⁺Levels

Cited by 223 publications

References 67 publications

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabinoids and Epilepsy

Molecular Targets of Cannabidiol in Neurological Disorders

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Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2+Levels

Cited by 223 publications

References 67 publications

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabinoids and Epilepsy

Molecular Targets of Cannabidiol in Neurological Disorders

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Resources

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Cannabidiol Targets Mitochondria to Regulate Intracellular Ca²⁺Levels