Cerebral ischemia

Stroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been proved truly effective in stroke treatment. Stroke my result in hypoxia, glutamate release and oxidative stress, etc. The purpose of this dissertation study is to evaluate the neuroprotective effects of four drugs (taurine, G-CSF sulindac and DETC-MeSO) on PC12 cell line or primary cortical neuronal cell culture, and to understand the protective mechanisms underlying in three stroke-related models : hypoxia, excessive glutamtate and oxidative stress. In the first part of this dissertation, we studied the neuroprotection of taurine against oxidative stress induced by H2O2 in PC12 cells. Our results show that extracellular taurine exerts a neuroprotective function by restoring the expression of Bcl-2 and downregulation of the three Endoplasmic Reticulum (ER) stress markers : GRP78, Bim and CHOP/GADD153, suggesting that ER stress can be provoked by oxidative stress and can be suppressed by taurine. In the second part, glutamate excitotoxicity-induced ER stress was studied with dose and time as variables in primary cortical neurons. The results demonstrate that glutamate excitotoxicity leads to the activation of three ER stress pathways (PERK, ATF6 and IRE1) by initiating PERK first, ATF6 second and IRE1 pathway last. The third part of this dissertation studied the robust and beneficial protection of taurine in cortical neurons under hypoxia/reoxygenation or glutamate toxicity condition. We found that taurine suppresses the up-regulation of GRP778, Bim, caspase-12 and GADD153/CHOP induced by excessive glutamate or hypoxia/reoxygenation, suggesting that taurine may exert a protective function against hypoxia/regeneration by reducing the ER stress.

The Effect of Sulindac was studied on an animal model of ischemic stroke. Sulindac, a non steroid anti inflammatory drug (NSAID) could protect cell death due to hypoxia/reoxygenation. This drug was given 2 days before and 24 hrs after ischemia until animals were sacrificed on 3rd or 11th day. Infarct size was measured for these animals. Sulindac induced Hsp 27 in ischemic penumbra and core on Day 3 & 11 with uncoated nylon suture which shows its cell-survival and anti-apoptotic activity. Also, it increased expression of cell survival markers such as Akt, Bcl2 & Grp 78 in ischemic penumbra and core. With silicon suture it reduced expression of Hsp 27 in ischemic penumbra and core, alleviating cell stress and having pro-survival and anti-stress effects. In conclusion sulindac may have excellent potential as neuro protective agent against oxidative stress in cerebral ischemia.