4.0 Cannabinoid receptor signaling and neurodegeneration
Glial cells are resident immune cells of the CNS and represent over 70% of the total cell population of the CNS (Bie et al., 2019). They function as the first line of defence against tissue insults such as inflammation. Glial cells include brain parenchymal-resident microglia, perivascular microglia, oligodendrocytes and astrocytes (Romero-Sandoval et al., 2008; Villacampa and Heneka, 2018). Depending on the type of stimuli received by microglia, they may assume either a neuroprotective phenotype or neurotoxic one (Schwartz et al., 2006). For instance, microglia are neuroprotective and their activities are central during the healing response in nerve transection models of glutamate injury (Schwartz et al., 2003). On the other hand, when primed with IFN-γ and then administered with LPS, microglia adopt a phenotype suited for defensive immunity, and hence become neurotoxic (Ashton and Glass, 2007). However, it has also been proposed that microglia may make a transition from neuroprotective to neurotoxic phenotype depending on the intensity of the neuronal insult and also duration of it (Zipp and Aktas, 2006).
Under normal physiological conditions, microglia modify synaptic structure and the local environment of neurons, thus play an essential role in induction and maintenance of synaptic plasticity, through processes such as phagocytosis (Tremblay and Majewska, 2011; Schafer and Stevens, 2013). As such, the intensity and nature of microglial-mediated synaptic pruning is central to the maintenance of synaptic structure or the destruction of the synapse and the onset of neurodegeneration (Paolicelli et al., 2011; Wake et al., 2013; Kettenmann et al., 2013). A wide array of noxious signals is capable of priming microglial cells, with subsequent transition of microglial phenotype from protective, anti-inflammatory to the rogue pro-inflammatory phenotype (Lan et al., 2017). The latter expresses several receptors such as purinergic P2X4 receptors and Toll-like receptors (TLRs) (Naguib et al., 2012). Activation of these receptors leads to downstream events that release several pro-inflammatory cytokines and chemokines with subsequent neuronal damage (Bie et al., 2018). Microglial activation and neuroinflammation is thus implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis, neuropathic pain and immunodeficiency virus-induced encephalitis (Ramirez et al., 2005; Benito et al., 2005; Bie et al., 2018).
It is a known fact that cannabinoids, such as 2-AG, stimulate neurogenesis in the adult brain (Ashton and Glass, 2007). This is supported by evidence from numerous studies, including a study by Jin et al. (2004) where defects associated with the process of neurogenesis in CB1-knockout mice were reported. Moreover, CB2 receptor stimulation is associated with upregulation of neurogenesis in neurological disease, leading to the production of new neurons in the hippocampus and the subventricular zone-olfactory bulb system (Ashton and Glass, 2007). In terms of microglial polarisation, changes in the levels of expression of CB2, but not CB1, closely correlate (Cabral and Marciano-Cabral, 2005). In a study by Cabral and Cabral (2005), the authors argued that CB2 expression is closely related to the multi-step activation of microglia.
In addition to stimulating proliferation and migration of the benign phenotype microglia, activation of CB2 receptors in microglia also blocks microglial differentiation to a neurotoxic phenotype. Thus, activation of the CB2 receptor inhibits microglial-mediated neuronal damage in a number of neurodegenerative disease models, including in β-amyloid and CD40L-induced oxidative damage, lipopolysaccharide-induced neuroinflammation and NMDA-injury models (Ehrhart et al., 2005). As proof of concept, the expression of markers of microglial activation following β-amyloid injections was inhibited by CB2 receptor stimulation with WIN 55,212-2, in an in vivo murine model of AD (Ramirez et al., 2005). In addition, in vitro CB2 receptor stimulation inhibits the release of pro-inflammatory mediators, including TNF-α, IL-1 and NO, from previously primed cytotoxic microglia phenotype. It, however, remains to be determined if this effect is as a result of reversal of microglia phenotype, from the cytotoxic pro-inflammatory to a neuroprotective anti-inflammatory phenotype (Ashton and Glass, 2007). Moreover, in a rodent model of multiple sclerosis, Rossi et al. (2013) demonstrated that genetic ablation of CB1 worsens neuronal loss in experimental autoimmune encephalomyelitis. In their study, AAT trinucleotide short tandem repeat polymorphism of gene that encodes CB1 receptor (located on chromosome 6) was associated with increased degeneration of gray matter in response to inflammatory lesions of the white matter, especially in areas crucial for cognitive function.