Cytisine is neuroprotective in female but not male 6 ‐hydroxydopamine lesioned parkinsonian mice and acts in combination with 17‐β‐estradiol to inhibit apoptotic endoplasmic reticulum stress in dopaminergic neurons

AbstractApoptotic endoplasmic reticulum (ER) stress is a major mechanism for dopaminergic (DA) loss in Parkinson ’s disease (PD). We assessed if low doses of the partial α4β2 nicotinic acetylcholine receptor (nAChR) agonist, cytisine attenuates apoptotic ER stress and exerts neuroprotection in substantia nigra pars compacta (SNc) DA neurons. Alternate day intraperitoneal injections of 0.2 mg/kg cytisine we re administered to female and male mice with 6‐hydroxydopamine (6‐OHDA) lesions in the dorsolateral striatum, which caused unilateral degeneration of SNc DA neurons. Cytisine attenuated 6‐OHDA‐induced PD‐related behaviors in female, but not in male mice. We also found significant reduction s in tyrosine hydroxylase (TH) loss within the lesioned SNc of female, but not male mice. In contrast to female mice, DA neurons within the lesioned SNc of male mice showed a cytisine‐induced pathological increase in the nuclear translocation of the pro‐apoptotic ER stress protein, C/EBP homolog ous protein (CHOP). To assess the role of estrogen in cytisine neuroprotection in female mice, we exposed primary mouse DA cultures to either 10 nM 17‐β‐estradiol and 200 nM cytisine or 10 nM 17‐β‐estradiol alone. 17‐β‐estradiol reduced expression of CHOP, while cytisine exposure redu ced 6‐OHDA‐mediated nuclear translocation of two other ER stress proteins, activating transcription factor 6 (ATF6) and x‐box binding protein 1 (XBP1), but not CHOP. Taken toget...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research