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.