Prospects for cannabinoid therapies in basal ganglia disorders

Abstract

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like D 9 -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB1 and CB2 receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB2 receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB2 receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB2 receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB2 receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB2 receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. LINKED ARTICLES

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

“…In the precise case of HD, it has been long suggested that the early and massive down-regulation of CB 1 receptors located on MSNs plays a pathogenic role in promoting disease onset and progression (12,33,34). Thus, as the CB 1 receptor couples to several cell-autonomous neuroprotective pathways (6,35), one might suppose that its down-regulation in MSNs would render these cells more susceptible to damage.…”

“…To assess the functional impact of the CB 1 receptor on glutamatergic and GABAergic signaling in a neurodegenerative-disease context, we conducted experiments in the R6/2 mouse, a well-established model of HD. This devastating disease constitutes so far the best paradigm to study the specific role of CB 1 receptors located on glutamatergic or GABAergic terminals because CB 1 receptors are expressed in the striatum at synapses established by neurons containing GABA (especially MSNs, the cells that primarily degenerate in HD) or glutamate (especially corticostriatal projecting neurons, which critically control MSN function) as transmitters, and play a key role in the control of motor behavior, one of the processes that is most typically affected in HD (11,12). Moreover, a remarkable down-regulation of CB 1 receptors has been documented as one of the earliest and most characteristic neurochemical alterations found in the MSNs of HD animal models (13,14) and patients with HD (15,16).…”

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

“…Accumulating evidence suggests that the cannabinoid system is a promising pharmacological target for the treatment of PD (49,50) and levodopa-associated motor complications (51,52). The CB 1 receptor regulates motor behavior in the basal ganglia via mediating both excitatory and inhibitory inputs to the SN reticulate and globus pallidus (53) as well as short-and long-term synaptic plasticity through suppressing the release of neurotransmitters, such as glutamate and GABA (54,55).…”

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

“…Cannabinoids have been postulated to increase neurogenesis in the adult brain, and to protect neurons from excitotoxicity, calcium influx, inflammation, and ischemia. These mechanisms have been postulated in the pathogenesis of Alzheimer's disease and, therefore, cannabinoids may have beneficial effects in this disease [4,7,[13][14][15]. Additional mechanisms of action, including activation of peroxisome proliferator-activated receptors and modulation of mitochondrial activity and oxidative stress, could also contribute to cannabinoid-induced neuroprotection [19][20][21].…”

“…Huntington's disease [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The neuroprotective effects of cannabinoids are mediated through CB1 receptors, located in neurons, which modulate neuronal function, and CB2 receptors, mostly located in microglia, which play an important role in neuroinflammation.…”