Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

Department of Psychology, Psychology Building, Ohio State University, Columbus, OH 43210, USA.
Neurobiology of aging (Impact Factor: 5.01). 07/2007; 29(12):1894-901. DOI: 10.1016/j.neurobiolaging.2007.04.028
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The number of activated microglia increase during normal aging. Stimulation of endocannabinoid receptors can reduce the number of activated microglia, particularly in the hippocampus, of young rats infused chronically with lipopolysaccharide (LPS). In the current study we demonstrate that endocannabinoid receptor stimulation by administration of WIN-55212-2 (2mg/kg day) can reduce the number of activated microglia in hippocampus of aged rats and attenuate the spatial memory impairment in the water pool task. Our results suggest that the action of WIN-55212-2 does not depend upon a direct effect upon microglia or astrocytes but is dependent upon stimulation of neuronal cannabinoid receptors. Aging significantly reduced cannabinoid type 1 receptor binding but had no effect on cannabinoid receptor protein levels. Stimulation of cannabinoid receptors may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer's disease.

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Available from: Yannick Marchalant, Oct 13, 2015
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    • "In these structures, NMDARs physically link to kinases, phosphatases, GPCRs, and other signaling molecules (Kim and Sheng, 2004; Sans et al., 2005). Immunocytochemical and ultrastructural studies have described the presence of CB1s in the post-synapse at both the spinal (Hohmann et al., 1999; Ong and Mackie, 1999; Salio et al., 2002) and supraspinal levels (Rodriguez et al., 2001; Kofalvi et al., 2005), where they co-localize with NMDARs (Marchalant et al., 2008). Co-immunoprecipitation assays performed on mouse cerebral cortical synaptosomes have also demonstrated the association between CB1 and NMDARs, concretely with NR1 subunits (Garzón et al., 2009; Sánchez-Blázquez et al., 2013b). "
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    ABSTRACT: The endocannabinoid system is widespread throughout the central nervous system and its type 1 receptor (CB1) plays a crucial role in preventing the neurotoxicity caused by activation of glutamate N-methyl-D-aspartate receptors (NMDARs). Indeed, it is the activity of NMDARs themselves that provides the demands on the endogenous cannabinoids in order to control their calcium currents. Therefore, a physiological role of this system is to maintain NMDAR activity within safe limits, thereby protecting neural cells from excitotoxicity. Thus, cannabinoids may be able to control NMDAR overactivation-related neural dysfunctions; however the major obstacles to the therapeutic utilization of these compounds are their psychotropic effects and negative influence on cognitive performance. Studies in humans have indicated that abuse of smoked cannabis can promote psychosis and even circumstantially precipitate symptoms of schizophrenia, although the latter appears to require a prior vulnerability in the individual. It is possible that cannabinoids provoke psychosis/schizophrenia reflecting a mechanism common to neuroprotection the reduction of NMDAR activity. Cannabinoids are proposed to produce such effect by reducing the pre-synaptic release of glutamate or interfering with postsynaptic NMDAR-regulated signaling pathways. The efficacy of such control requires the endocannabinoid system to apply its negative influence in a manner that is proportional to the strength of NMDAR signaling. Thus, cannabinoids acting at the wrong time or exerting an inappropriate influence on their receptors may cause NMDAR hypofunction. The purpose of the present review is to draw the attention of the reader to the newly described functional and physical CB1-NMDAR association, which may elucidate the scenario required for the rapid and efficacious control of NMDAR activity. Whether alterations in these mechanisms may increase NMDAR hypofunction leading to vulnerability to schizophrenia will be outline
    Frontiers in Pharmacology 01/2014; 4:169. DOI:10.3389/fphar.2013.00169 · 3.80 Impact Factor
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    • "Three potential interventions have been identified using CB2R as target [24]. First, stimulation of CB2 receptors suppresses microglial activation [33] [34] second, a CB2 receptor agonist such as JWH-015 is capable of inducing the removal of native beta-amyloid [25] [31] [35] and third, CB2 receptor agonists suppress the neuroinflammatory process [36]. Taken together, these results suggest that CB1 receptor agonists may interrupt the mechanism of excitotoxicity and CB2 receptor agonists may suppress neuroinflammation and lead to plaque removal. "
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    ABSTRACT: Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.
    European Journal of Medicinal Chemistry 12/2013; 73C:56-72. DOI:10.1016/j.ejmech.2013.11.026 · 3.45 Impact Factor
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    • "Thus, besides interacting with distant signaling pathways, cannabinoids can also directly affect the open probability of the NMDAR calcium channel. Immunocytochemical and ultrastructural studies demonstrated the presence of CNR1s in the post-synapse at both the spinal [12-14] and supraspinal level [15,16], where they co-localize with NMDARs and PSD95 proteins [5,17]. Indeed, co-immunoprecipitation assays performed ex vivo on mouse cerebral cortical synaptosomes and in vitro studies with recombinant proteins revealed the association between CNR1s and NMDARs [5,18]. "
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    ABSTRACT: G protein-coupled receptors (GPCRs) are the targets of a large number of drugs currently in therapeutic use. Likewise, the glutamate ionotropic N-methyl-D-aspartate receptor (NMDAR) has been implicated in certain neurological disorders, such as neurodegeration, neuropathic pain and mood disorders, as well as psychosis and schizophrenia. Thus, there is now an important need to characterize the interactions between GPCRs and NMDARs. Indeed, these interactions can produce distinct effects, and whereas the activation of Mu-opioid receptor (MOR) increases the calcium fluxes associated to NMDARs, that of type 1 cannabinoid receptor (CNR1) antagonizes their permeation. Notably, a series of proteins interact with these receptors affecting their responses and interactions, and then emerge as novel therapeutic targets for the aforementioned pathologies. We found that in the presence of GPCRs, the HINT1 protein influences the activity of NMDARs, whereby NMDAR activation was enhanced in CNR1+/+/HINT1-/- cortical neurons and the cannabinoid agonist WIN55,212-2 provided these cells with no protection against a NMDA insult. NMDAR activity was normalized in these cells by the lentiviral expression of HINT1, which also restored the neuroprotection mediated by cannabinoids. NMDAR activity was also enhanced in CNR1-/-/HINT1+/+ neurons, although this activity was dampened by the expression of GPCRs like the MOR, CNR1 or serotonin 1A (5HT1AR). The HINT1 protein plays an essential role in the GPCR-NMDAR connection. In the absence of receptor activation, GPCRs collaborate with HINT1 proteins to negatively control NMDAR activity. When activated, most GPCRs release the control of HINT1 and NMDAR responsiveness is enhanced. However, cannabinoids that act through CNR1 maintain the negative control of HINT1 on NMDAR function and their protection against glutamate excitotoxic insult persists.
    Molecular Brain 10/2013; 6(1):42. DOI:10.1186/1756-6606-6-42 · 4.90 Impact Factor
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