CB2, PPAR-γ y GPR55 como dianas farmacológicas para un tratamiento anti-inflamatorio y neuroprotector en la enfermedad de ParkinsonCB2, PPAR-γ and GPR55 as pharmacological targets for an anti-inflammatory and neuroprotective treatment of Parkinson's disease

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disorder which courses with hypokinetic symptoms due to the selective death of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the consequent dopaminergic denervation of the striatum. This disease is also a proteinopathy, as one of its features is the presence of aggregates of misfolded proteins, mainly α-synuclein, known as Lewy bodies (LB). The etiology of PD remains unknown, but several environmental and genetic risk factors have been described, together with aging as the main one. The main symptoms of PD are bradykinesia, rigidity, and resting tremor, usually determinant for the diagnosis, which appear when more than 50% of the dopaminergic neurons are already dead. However, there are non-motor symptoms such as sleep disturbances, mood symptoms, gastrointestinal problems, and olfactory dysfunction, which may be prodromal and could be useful for an early diagnosis. The pathological events that contribute to the neuronal death include not only protein aggregation, but also neuroinflammation, mitochondrial dysfunction, oxidative stress, and excitotoxicity. These mechanisms are known to be interconnected, worsening the dopaminergic neurodegeneration which disturbs the basal ganglia circuitry, preventing a correct motor functioning. The most frequent treatment is the replacement of dopamine levels, mainly with levodopa (L-DOPA), which recovers the mobility of the patients in the short term but causes irreversible dyskinesias after several years. This makes urgent the need of a disease-modifying treatment, and given the multifactorial pathophysiology of PD, we propose the use of pleiotropic molecules which can be effective at several levels, such as cannabinoids...