Research Topic

The CB2 Cannabinoid System: a New Strategy in Neurodegenerative Disorder and Neuroinflammation

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The endocannabinoid system consist of cannabinoid receptors CB1 and CB2, endogenous ligands, and enzymes responsible for their synthesis and degradation. CB1 and CB2 are Gi/o-coupled receptors; CB1 is mostly localized at central nervous system, in neurons and glial cells, where they are responsible for ...

The endocannabinoid system consist of cannabinoid receptors CB1 and CB2, endogenous ligands, and enzymes responsible for their synthesis and degradation. CB1 and CB2 are Gi/o-coupled receptors; CB1 is mostly localized at central nervous system, in neurons and glial cells, where they are responsible for memory, cognition, emotion, motor control, feeding and pain perception. CB2 receptors are present in the cells of immune system, where they regulate cell migration and cytokines release, and in the nervous system, in some neurons and in microglia (Cabraland Griffin-Thomas,2009). The most representative endocannabinoids are arachidonoylethanolamine (AEA) or anandamide, and 2-arachidonoylglycerol (2-AG), derived from the degradation of membrane phospholipids (Piomelli, 2003). Endocannabinoids are neurotransmitters synthesised and released by neurons but acting as retrograde messengers and not accumulating in synaptic vesicles. Several evidences demonstrated the potential therapeutic utility of cannabinoid in neurodegenerative disease. In AD, studies performed in AD cellular and animal models led to the identification of direct and indirect neuroprotective mechanisms of CB2 ligands. As for indirect mechanisms, in vitro and in vivo studies showed that some cannabinoid ligands such as AEA, 2-AG, and noladin confer neuroprotection by increasing the viability of neurons after exposure to toxic Aβ species. CB2 selective ligands were able to improve cognitive response in two different transgenic mouse models of brain amyloidosis; cannabidiol were found able to prevent ROS production, lipid peroxidation and to induce a decreased level of NO and the expression of the enzyme responsible for NO synthesis, iNOS. Moreover, CB2 ligands enhanced the levels of superoxide-dismutases SOD1 and SOD2 in the plaques suggesting the involvment of CB2 sites in the reduction of oxidative stress. Cannabinoids also increase BDNF (brain-derived neurotrophic factor), the neurotrophin responsible for neurogenesis, for neuronal plasticity and conferring neuroprotection against excitotoxicity. This neurotrophin is reduced in AD brains. As for direct mechanisms, the stimulation of CB2 sites is responsible for the Aβ removal by human macrophages and for Aβ transport through the choroid plexus. Moreover, CB2 sites are overexpressed in Aβ plaque-associated microglia and CB2 agonists were found able to to block the microglia activation due to Aβ inhibiting inflammation in AD. All these findings suggest cannabinoid ligands as potential therapeutic strategy in neurodegeneration as they exert an anti-oxidant and anti-inflammatory activity, and also are directly involved in AD pathogenesis since modulate several factors such as altered Aβ metabolism and neurotrophic deficencies. In this Research topic it should be deepened and elucidated the potential of CB2 ligands in neurodegeneration therapy.


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