2-Pentadecyl-2-Oxazoline reduces neuroinflammatory environment in the MPTP model of Parkinson Disease

Parkinson disease (PD) is the most common chronic neurodegenerative movement disorder. It is characterized by the presence of activated microglia and reactive astrocytes in the brain parenchyma, accumulation of α-synuclein (α-syn), and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to depletion of striatal dopamine (DA). Notwithstanding intense improvements in the management of PD current therapeutic strategies, including DA replacement therapy, only provide temporary relief of motor symptoms. One of the most important pathological marker of PD is chronic neuroinflammation. Glial cell activation, microglia and astrocytes are understood to play serious roles in the neuroinflammatory processes connected with PD. Growing evidence indicates that the nuclear factor E2-related factor 2 Nrf2 () signalling pathway plays a key role in neuroinflammation, hyperoxia, and impaired macrophage function. Nrf2 was originally shown to bind the antioxidant responsive element (ARE) and control expression of oxidative stress-inducible enzymes and detoxification genes, in response to electrophilic and reactive oxygen species-producing agents. Other studies propose that Nrf2 suppresses inflammation by inhibiting nuclear factor (NF)-κB activation through regulation of redox balance. However, Nrf2 appears to regulate a far greater gene expression response, including genes involved in protein homeostasis, such as chaperones and proteasome subunits. The endocannabinoid system is an endogenous signalling system that regulates several pathological and physiological conditions, such as inflammation, analgesia, addictive behaviour, pain and neurodegenerative disorders such as multiple sclerosis and PD. One of the main protagonists of the family of endocannabinoids, on which research in recent years has largely focused, is N-palmitoylethanolamine (PEA), an endocannabinoid congener, that is considered to be the prototype of ALIAmide family, known for its important analgesic, anti-inflammatory and neuroprotective properties.