Progesterone induced neuroprotection in reperfusion promoted mitochondrial dysfunction following focal cerebral ischemia in rats

Abstract

Organelle damage and increases in mitochondrial permeabilization are key events in the development of cerebral ischemic tissue injury because they cause both modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetic processes can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found to be neuroprotective in various models of neurological diseases, through a number of mechanisms. This influenced us to investigate the possible role of P4 in the mitochondria-mediated neuroprotective mechanism in an ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg body weight) or vehicle at 1 h post-occlusion followed by subcutaneous injections at 6, 12 and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals. Staining of isolated brain slices from P4-treated rats with 2,3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. P4 treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that P4 has a positive effect on mitochondrial bioenergetics. In conclusion, these results demonstrate that P4 treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies.

Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases

“…While the mitochondrial effects of testosterone are not well documented, several pharmacological studies have shown that exogenous administration of 17β-estradiol and/or progesterone increases RC function and decreases oxidative stress in brain mitochondria (reviewed in Chen et al, 2009a , b ; Rettberg et al, 2014 ; Gaignard et al, 2017 ). It has also been demonstrated that these mitochondrial effects contribute to the neuroprotective properties of sex steroids after brain injury (Robertson et al, 2006 ; Guo et al, 2012 ; Robertson and Saraswati, 2015 ; Webster et al, 2015 ; Gaignard et al, 2016 ; Yousuf et al, 2016 ; Andrabi et al, 2017 ).…”

N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity

“…Concerning the second studied mechanism of the CIPN, the structure of the mitochondria in the axoplasm was well preserved in the use of both NAC and progesterone. The ability of the NAC and progesterone to restore and preserve the normal mitochondrial function was proved in many studies [3,37,42]. The normal mitochondrial function is important as the mitochondrial dysfunction is the main cause of redox imbalance and apoptosis in peripheral neurons [21].…”

Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone‐treated mice

“…Interestingly, mitochondrion is a target of progestin action. Pharmacological studies describe an increase in electron transport chain and a decrease oxidative stress after exogenous administration of progesterone and oestrogen . Therefore, steroids may produce a “feed forward” mechanism stabilising mitochondria and stimulating their own synthesis.…”