The Development of Cannabinoid CBII Receptor Agonists for the Treatment of Central Neuropathies

Abstract

Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer's disease and Parkinson's disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR).

Pharmacological Activation/Inhibition of the Cannabinoid System Affects Alcohol Withdrawal-Induced Neuronal Hypersensitivity to Excitotoxic Insults

“…Among the proposed mechanisms of cannabinoid-receptor mediated neuroprotection, two are particularly relevant for the neurotoxicity caused by alcohol dependence and withdrawal: the inhibition of the presynaptic release of glutamate [16] and the inhibition of NMDA-induced Ca 2+ influx [17]. It appears well-demonstrated that CB1 receptors are involved in these two neuroprotective properties of cannabinoid agonists and although HU-210 is a non-selective cannabinoid agonist, we assume that, in our experiments, HU-210 preferentially acts through the activation of CB1 receptors because -consistent with the suggestion that CB2 receptors are essentially present in glial cells [18] and considering the high purity of our neuronal cultures (thanks to the use of an anti-mitotic agent)- no mRNA encoding for CB2 receptors were detected in our cultures (data not shown).…”

CB1 and CB2 contribute to antinociceptive and anti-inflammatory effects of electroacupuncture on experimental arthritis of the rat temporomandibular joint

“…Rivers and Ashton (2010) stated that this finding is not unexpected because microglial cells are resident immune cells of the CNS derived from the same lineage as peripheral immune cells. Microglial cell activation releases several mediators of pain, including TNF␣, IL-1, and IL-6 (Shan et al 2007), and various other substances that increase nociceptive transmission (Watkins et al 2001;Waltkins and Maier 2003;DeLeo et al 2004).…”

Brain CB2 Receptors: Implications for Neuropsychiatric Disorders

“…Cannabinoid compounds, plant-derived, synthetic and endogenous, are well known to elicit potent effects on inflammation, both peripherally and centrally. The presence of CB 2 receptors on glia and neurons in the brain, has prompted several groups to investigate the role of this receptor in neuroinflammation and neuroprotection, a topic which has been covered in detail by several recent reviews [43,44,45,46,47,48,49]. This body of evidence suggests that CB 2 receptor activation elicits glial-dependant anti-inflammatory effects, thereby reducing neuroinflammation associated with several neurodegenerative diseases.…”

“…Similarly, GlaxoSmithKline have also completed Phase 2 clinical trials evaluating the effects of the selective CB 2 agonist GW842166, in osteoarthritis [41] and dental pain [42], although the results of these studies have not been published to date. Identification of CB 2 receptors in the central nervous system has also led to increasing investigation into its involvement in neuroimmunological and neurodegeneratative disorders, topics which have been covered in detail by several recent reviews [43,44,45,46,47,48,49,50]. The present review will provide an overview of the evidence demonstrating the presence of functional CB 2 receptors in the brain, the role of this receptor in neurophysiology and highlight the potential involvement of these receptors in neuropsychiatric disorders.…”