Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects

Jiang, Wen; Zhang, Yun; Xiao, Lan; Cleemput, Jamie Van; Ji, Shaoping; Bai, Guang; Zhang, Xia

doi:10.1172/jci25509

Cited by 461 publications

(363 citation statements)

References 58 publications

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“…For example, neurogenesis in both embryonic and cultured adult hippocampal neural stem and progenitor cells has been shown via the activation of GPCRs, CB 1 receptors and ERK signalling by CBD and other synthetic cannabinoids (Jiang et al, 2005). Furthermore, CBD has been implicated in CB 1 receptor‐mediated proliferation and maturation of progenitor cells (Wolf et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…4,5,49 Since depressive disorders are often manifestations of adult hypothyroidism, we carried out the Porsolt or forced swimming test in P120 E, H, and R rats. In this paradigm, rats forced to swim in a situation from which they cannot escape, rapidly become immobile, floating in an upright position and making only small movements to keep their heads above the water.…”

Section: Neurogenesis In the Adult Dg Is Influenced By Thyroid Hormonmentioning

confidence: 99%

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

et al. 2006

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Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and psychiatric diseases. Specifically, thyroid state alterations in the adult are related to psychological changes and mood disorders as depression. The dentate gyrus of the hippocampal formation undergoes neurogenesis in adult mammals including humans. Recent evidence suggests that depressive disorders and their treatment are tightly related to the number of newly born neurons in the dentate gyrus. We have studied the effect of thyroid hormones (TH) on hippocampal neurogenesis in adult rats in vivo. A short period of adultonset hypothyroidism impaired normal neurogenesis in the subgranular zone of the dentate gyrus with a 30% reduction in the number of proliferating cells. Hypothyroidism also reduced the number of newborn neuroblasts and immature neurons (doublecortin (DCX) immunopositive cells) which had a severely hypoplastic dendritic arborization. To correlate these changes with hippocampal function, we subjected the rats to the forced swimming and novel object recognition tests. Hypothyroid rats showed normal memory in object recognition, but displayed abnormal behavior in the forced swimming test, indicating a depressive-like disorder. Chronic treatment of hypothyroid rats with TH not only normalized the abnormal behavior but also restored the number of proliferative and DCX-positive cells, and induced growth of their dendritic trees. Therefore, hypothyroidism induced a reversible depressive-like disorder, which correlated to changes in neurogenesis. Our results indicate that TH are essential for adult hippocampal neurogenesis and suggest that mood disorders related to adult-onset hypothyroidism in humans could be due, in part, to impaired neurogenesis.

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“…Adult rats treated with an AEA analogue show significantly decreased neurogenesis in dentate gyrus, and this is increased by a CB1 antagonist (Rueda et al, 2002). However, other evidence indicates that chronic treatment with an endocannabinoid agonist increases hippocampal neurogenesis in adult rats (Jiang et al, 2005), and CB1 receptor-knockout mice show significant reductions in neurogenesis (Jin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

et al. 2016

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Running title: EPA, but not DHA induces proliferation in NSCs Abbreviations: AA, Arachidonic acid, AEA, anandamide, DHA. Docosahexaenoic acid; EPA, eicosapentaenoic acid, 2-AG, 2-arachidonylglycerol 2 Title: Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1 deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1 signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1 deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.

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Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects

Cited by 461 publications

References 58 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

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

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