Withania modulation of Cannabinoid receptors?
"Although the endocannabinoid system has been known to interact with other systems like hypocretin, dopaminergic, and adenosinergic systems (Fernandez-Ruiz et al., 2010; Ferre et al., 2010; Tebano et al., 2012), its interaction with the opioid system is now well established (Fattore et al., 2005; Vigano et al., 2005; Robledo et al., 2008; Trigo et al., 2010). These two systems share neuroanatomical, neurochemical, and pharmacological, characteristics, this phenomenon is yet less well documented for the CB2 receptor. Figure Figure11 illustrates brain structures expressing CB1 receptors and depicts expression level of mu opioid receptors in these areas."
"Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies."
"Withania somnifera, or Ashwagandha, is an evergreenshrub native of the Indian subcontinent which spontan-eously grows also in the Mediterranean basin [15]. Itsincreasing attractiveness is mostly due to the anti-inflammatory [1, 8] and anti-cancer [1, 6] properties, butalso to a number of central effects related to stress [8],anxiety [16] and neurodegenerative disorders [8, 17].In this frame, it is worth noting that Withanolidesand Withaferin A, abundantly present in Withaniasomnifera roots, have been reported to interact withcholinergic mechanisms [18] and also with Nuclearfactor-κB[19–21]
The standardized Withania somnifera Dunal root extract alters basal and morphine-induced opioid receptor gene expression changes in neuroblastoma cells (PDF Download Available). Available from: https://www.research...oblastoma_cells [accessed Jan 22 2018]."
"https://onlinelibrar.../bph.12492/full Cannabinoids and adult neurogenesis
Adult neurogenesis is the process by which new neurons are generated and integrated into the developed brain. Regulation of neurogenesis is strictly controlled through a number of different factors such as adrenal and sex hormones, neurotransmitter systems, trophic factors and inflammatory cytokines. The formation of new neurons and neuronal connections may prove vital to sustaining neuronal function in neurodegenerative disorders where neurogenesis is impaired such as AD and HD (Molero et al., 2009; Crews et al., 2010). The eCB system has been closely linked to the process of adult neurogenesis. DGLα and DGLβ synthesize the endocannabinoid 2AG, and DGLα and DGLβ null mice have an 80 and 50% reduction in 2AG respectively. These transgenic mice were shown to have impaired neurogenesis, believed to be as a result of the loss of 2AG-mediated transient suppression of GABAergic transmission at inhibitory synapses (Gao et al., 2010). Furthermore, mice lacking CB1 receptors displayed an almost 50% reduction in neurogenesis in the dentate gyrus and subventricular zone when compared to wild type. In line with this, the mixed CB1/CB2 receptor agonist WIN 55212-2 enhanced BrdU incorporation into murine neuronal culture in a CB1 receptor-mediated fashion (Kim et al., 2006b). CB1 receptor-mediated stimulation of adult neurogenesis has been shown to act through its opposition of the antineurogenic effect of nitric oxide (Kim et al., 2006b; Marchalant et al., 2009). Neuronal precursor cell proliferation and the number of migrating neurons have been shown to increase in neurogenic regions in response to seizure, ischaemia and excitotoxic and mechanical lesions indicating a possible contributing factor in the repair of lesioned circuits (Gould and Tanapat, 1997; Arvidsson et al., 2001; Parent et al., 2002; Lie et al., 2004). KA-induced neural progenitor proliferation is reduced in CB1 receptor deficient mice as well as in wild-type mice administered with the selective CB1 receptor antagonist SR141716A. This effect was attributed to the CB1-dependent expression of basic fibroblast growth factor and epidermal growth factor (Aguado et al., 2007). BDNF is vital for the survival of new neurons and is significantly reduced in neurodegenerative conditions such as HD (Zuccato and Cattaneo, 2007). De March et al. (2008) have shown that 2 weeks post-excitotoxic lesion in rats, transient up-regulation of BDNF coincides with higher binding activity and protein expression of CB1 receptor. This is believed to be an attempt to rescue the striatal neuronal population. In a reciprocal fashion, BDNF (10 ng mL−1) was shown in vitro to increase neuronal sensitivity to the endocannabinoids 2AG and noladin ether as measured by the phosphorylation of Akt (Maison et al., 2009). Indeed, CB1 receptor activation has been implicated in neural precursor proliferation and neurogenesis while CB1 and CB2 receptor activation is involved in neural progenitor cell proliferation, both of which are vital to the generation and survival of new neurons (Palazuelos et al., 2006; Aguado et al., 2007)."
" https://link.springe...?no-access=true Arabinogalactan is a polysaccharide isolated from the roots of the medicinal plant Withania somnifera L. It contains 65 % arabinose and 18 % galactose. The aim of the present study was to evaluate the antitussive activity of arabinogalactan in conscious, healthy adult guinea pigs and the role of the opioid pathway in the antitussive action. A polysaccharide extract was given orally in a dose of 50 mg/kg. Cough was induced by an aerosol of citric acid in a concentration 0.3 mol/L, generated by a jet nebulizer into a plethysmographic chamber. The intensity of cough response was defined as the number of cough efforts counted during a 3-min exposure to the aerosol. The major finding was that arabinogalactan clearly suppressed the cough reflex; the suppression was comparable with that of codeine that was taken as a reference drug. The involvement of the opioid system was tested with the use of a blood-brain barrier penetrable, naloxone hydrochloride, and non-penetrable, naloxone methiodide, to distinguish between the central and peripheral mu-opioid receptor pathways. Both opioid antagonists acted to reverse the arabinogalactan-induced cough suppression; the reversion was total over time with the latter antagonist. We failed to confirm the presence of a bronchodilating effect of the polysaccharide, which could be involved in its antitussive action. We conclude that the polysaccharide arabinogalactan from Withania somnifera has a distinct antitussive activity consisting of cough suppression and that this action involves the mu-opioid receptor pathways."
"ASH-WEX and FIV inhibited the LPS-induced inflammatory pathway proteins As the change in the cellular morphology is associated with the functional activity of the microglial cells, we further studied the expression of various proteins associated with LPS-induced inflammatory pathways. Immunostaining for NFkB and AP1 showed enhanced expression of these proteins with higher nuclear translocation in LPS-treated primary microglial cells as compared to control. However, both ASH-WEX and FIV pretreatment to these cells downregulated the expression of these molecules and also their translocation to nucleus"
" https://link.springe...1064-012-0716-2 here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB1 receptor neutral antagonist AM4113, but not the CB2 antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB1 receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin"
"Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons
Endocannabinoid, particularly 2-arachidonoyl glycerol (2-AG), signaling has recently emerged as a molecular determinant of neuronal migration and synapse formation during cortical development. However, the cell type speci ficity and molecular regulation of spatially and temporally confined morphogenic 2-AG signals remain unexplored. Here, we demonstrate that genetic and pharmacological manipulation of CB1 cannabinoid receptors permanently alters cholinergic projection neuron identity and hippocampal innervation. We show that nerve growth factor (NGF), implicated in the morphogenesis and survival of cholinergic projection neurons, dose-dependently and coordinately regulates the molecular machinery for 2-AG signaling via tropomyosine kinase A receptors in vitro. In doing so, NGF limits the sorting of monoacylglycerol lipase (MGL), rate limiting2-AG bioavailability, to proximal neurites, allowing cell-autonomous 2-AG signaling at CB1 cannabinoid receptors to persist at atypical locations to induce superfluous neurite extension. We find that NGF controls MGL degradation in vitro and in vivo and identify the E3 ubiquitin ligase activity of breast cancer type 1 susceptibility protein (BRCA1) as a candidate facilitating MGL’s elimination from motile neurite segments, including growth cones. BRCA1 inactivation by cisplatin or genetically can rescue and reposition MGL, arresting NGF-induced growth responses. These data indicate that NGF can orchestrate endocannabinoid signaling to promote cholinergic differentiation and implicate BRCA1 in determining neuronal morphology."
