Formoterol attenuated mitochondrial dysfunction in rotenone-induced Parkinson's disease in a rat model: Role of PINK-1/PARKIN and PI3K/Akt/CREB/BDNF/TrKB axis.

β2-adrenoreceptors (β2AR have been identified recently as regulators of the α-synuclein gene (SNCA), one of the key milieus endorsed in injury of dopamine neurons in Parkinson's disease (PD). Accumulation of α-synuclein leads to mitochondrial dysfunction via downregulation of mitophagy proteins (PINK-1 and PARKIN) and inhibition of mitochondria biogenesis (PGC-1α) along with an increase in the master inflammatory regulator NF-κB p65 production that provokes neurodegeneration and diminishes neuroprotective signaling pathway (PI3k/Akt/CREB/BDNF). Recently, formoterol exhibited a promising neuroprotective effect against neurodegenerative conditions associated with brain inflammation. Therefore, the present investigation aims to unveil the possible neuroprotective activity of formoterol, β2AR agonist, against rotenone-induced PD in rats. Rats received rotenone (1.5 mg/kg; s.c.) every other day for 3 weeks and cured with formoterol (25 μg/kg/day; i.p.) 1 hr. after rotenone administration, starting from day 11. Formoterol treatment succeeded in upregulating β2-adrenoreceptor expression in PD rats and preserving the function and integrity of dopaminergic neurons as witnessed by enhancement of muscular performance in tests, open field, grip strength-meter, and Rotarod, besides the increment in substantia nigra and striatal tyrosine hydroxylase immunoexpression. In parallel, formoterol boosted mitophagy by activation of PINK1 and PARKIN and preserved mitochondrial membrane potential. Additionally, formoterol stimulated the neuro-survival signaling axis via stimulation of PI3k/pS473-Akt/pS133-CREB/BDNF cascade to attenuate neuronal loss. Noteworthy formoterol reduces neuro-inflammatory status by decreasing NFκBp65 immunoexpression and TNF-α content. Finally, formoterol's potential as a stimulant therapy of mitophagy via the PINK1/PARKIN axis and regulation of mitochondrial biogenesis by increasing PGC-1α to maintain mitochondrial homeostasis along with stimulation of PI3k/Akt/CREB/BDNF axis.