Priya Arunachalam

Introduction. Stroke is characterized by a sudden loss in neurological function due to a vascular event. Ischemic stroke, a reduction in focal cerebral blood flow due to obstruction, accounts for 87% of all strokes. The loss of blood flow leads to a deprivation of nutrients such as glucose and oxygen; at the location of the infarct, a necrotic core forms.¹ Surrounding the infarct is a hypo-perfused region maintained by collateral flow. This region is called the penumbra. After hours or days of reduced oxygen delivery, the penumbral neurons experience decreased ATP production and subsequent membrane potential changes as ATP-dependent ion pumps fail to work.² Disrupted membrane potential leads to mitochondrial membrane destabilization and the release of cytochrome C from the inner mitochondrial membrane, directing the cell towards apoptosis. Current treatments aim to reperfuse the tissue as soon as possible in order to reduce neurological damage due to tissue loss. However, because of the potential for reperfusion injury in the penumbra, several studies have attempted to identify treatments to reduce apoptosis due to mitochondrial destabilization. Polydatin and di-3n-butylphthalide (NBP) are two treatments that have been studied because of their ability to stabilize mitochondria and prevent apoptosis in animal models.^3-6 These findings could have translational implications in protecting the penumbral neurons and consequential reduction in loss of neurological function. Methods. Studies involving polydatin or NBP separated adult rats into a sham-operated group, sham-operated with treatment or pre-treatment, middle cerebral artery occlusion, and middle cerebral artery occlusion with treatment or pre-treatment.^3-6 Transmission Electron Microscopy and H&E stained images were collected in addition to Western Blots against inflammatory mediators such as JNK and p38. Results. In their respective studies, both polydatin and NBP demonstrated the ability to induce neuroprotection in animal models by reducing neuroinflammation and preventing apoptosis.^3-6 Inflammatory mediators were down-regulated on the Western Blots. Mitochondrial structure, membrane integrity, and membrane potential were maintained upon tissue analysis. Conclusions. Studies have found that treatments such as polydatin and NBP can leverage the role of mitochondria to reduce loss of penumbral neurons in animal models. However, it remains to be seen if the results in the animal models can be replicated in clinical research. The translational application of these treatments requires further investigation to determine the timing of treatment.

1. Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biology. 2018;16:263–275. doi:10.1016/j.redox.2018.03.002
2. Yuan J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14(4):469–477. doi:10.1007/s10495-008-0304-8
3. Gao Y, Chen T, Lei X, et al. (2016). Neuroprotective effects of polydatin against mitochondrial-dependent apoptosis in the rat cerebral cortex following ischemia/reperfusion injury. Molecular Medicine Reports. 2016:5481-5488. Published 2016 Nov 11. doi:10.3892/mmr.2016.5936
4. Shah FA, Kury LA, Li T, Zeb A, Koh PO, Liu F, Zhou Q, Hussain I, Khan AU, Jiang Y and Li S (2019) Polydatin Attenuates Neuronal Loss via Reducing Neuroinflammation and Oxidative Stress in Rat MCAO Models. Front. Pharmacol. 10:663. doi: 10.3389/fphar.2019.00663
5. Xu ZQ, Zhou Y, Shao BZ, Zhang JJ, Liu C. (2017). The Efficacy and Safety of DL-3-N-Butylphthalide on Progressive Cerebral Infarction. Am J Chin Med. 2019;47:507–525. doi: 10.1142/S0192415X19500265.
6. Yan R., Wang S. J., Yao G. T., Liu Z., Xiao N. (2017). The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur. Rev. Med. Pharmacol. Sci. 21 (22), 5275–5282. 10.26355