The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis

Abstract

Endocannabinoids are lipid signaling mediators that exert an important neuromodulatory role and confer neuroprotection in several types of brain injury. Excitotoxicity and stroke can induce neural progenitor (NP) proliferation and differentiation as an attempt of neuroregeneration after damage. Here we investigated the mechanism of hippocampal progenitor cell engagement upon excitotoxicity induced by kainic acid administration and the putative involvement of the CB 1 cannabinoid receptor in this process. Adult NPs express kainate receptors that mediate proliferation and neurosphere generation in vitro via CB 1 cannabinoid receptors. Similarly, in vivo studies showed that excitotoxicity-induced hippocampal NPs proliferation and neurogenesis are abrogated in CB 1 -deficient mice and in wildtype mice administered with the selective CB 1 antagonist rimonabant (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide; SR141716). Kainate stimulation increased basic fibroblast growth factor (bFGF) expression in cultured NPs in a CB 1 -dependent manner as this response was prevented by rimonabant and mimicked by endocannabinoids. Likewise, in vivo analyses showed that increased hippocampal expression of bFGF, as well as of brain-derived neurotrophic factor and epidermal growth factor, occurs upon excitotoxicity and that CB 1 receptor ablation prevents this induction. Moreover, excitotoxicity increased the number of CB 1 ؉ bFGF ؉ cells, and this up-regulation preceded NP proliferation. In summary, our results show the involvement of the CB 1 cannabinoid receptor in NP proliferation and neurogenesis induced by excitotoxic injury and support a role for bFGF signaling in this process.

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…Lastly and apart from the acute phase, both stroke and TBI have in common a chronic phase characterized by severe functional sequelae. This late phase offers, at least theoretically, a broader window for promoting repair and decreasing disability, in which there might be some room for cannabinoids based on their capability to induce proliferation of neural progenitors cells [40,41], their differentiation and migration at lesioned sites (Moro et al, unpublished results), or the differentiation of oligodendrocyte precursor cells to produce remyelination [42]-all these possibilities have already been investigated in experimental brain ischemia. The neuroprotective and neurorepair effects of cannabinoids in stroke and TBI may be facilitated by the responses experienced by endocannabinoids and their receptors and enzymes during the progression of both pathological conditions.…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…Moreover, transactivation can occur via cytosolic tyrosine kinases of the Src family and this mechanism may influence interneuron migration [20]. Growth factor levels are also regulated by cannabinoid signalling under different neurodegenerative paradigms, such as hippocampal and striatal excitotoxicity, in which BDNF, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) are tuned by CB 1 receptors [68][69][70]. Reciprocally, FGF receptors promote axonal growth and guidance via DAGL activation and 2AG generation [71].…”

Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis

“…11 Indeed, endocannabinoids have been already reported to promote cell proliferation of neural progenitor cells through CB1 receptor. 33,34 The role of the basic signaling of endocannabinoids lipid mediators in the angiogenic process has not yet been investigated. The present study arises from the observation that CB1 receptor expression is induced during angiogenesis in endothelial cells and that anandamide stimulated bFGF-induced proliferation in the nanomolar physiologic range.…”

“…17 Indeed, proliferation-promoting functions of CB1 receptors have been already reported in neurogenesis, that is impaired in mice lacking CB1 and in wild-type mice administered with CB1 antagonist, implying that an endogenous signaling through this receptor promotes basal levels of neurogenesis in vivo. 33,34 Furthermore, an antiproliferative action of CB1 antagonism in thyroid, mantle cell lymphoma, and breast cancers, 25-27 as well as in adipocytes and in hepatic myofibroblasts has been demonstrated. 10,46 As here showed, also CB1 receptor knockdown or pharmacologic antagonism inhibits angiogenesis in vitro and in vivo, suggesting that CB1 signaling could contribute to the proliferative response elicited by angiogenic factors, thus regulating the angiogenic process in physiologic and/or pathologic conditions.…”