Tetramethylpyrazine Protects Against Early Brain Injury and Inhibits the PERK/Akt Pathway in a Rat Model of Subarachnoid Hemorrhage

Abstract

Neuronal apoptosis is a potentially fatal pathological process that occurs in early brain injury (EBI) after subarachnoid hemorrhage (SAH). There is an urgent need to identify effective therapeutics to alleviate neuronal apoptosis. Tetramethylpyrazine (TMP), as an important component of the Chinese traditional medicinal herb Ligusticum wallichii, has been widely used in China to treat cerebral ischemic injury and confer neuroprotection. In the present work, we investigate whether TMP can reduce EBI following SAH in rats, specifically via inactivating the PERK/Akt signaling cascade. One hundred twenty-five male Sprague-Dawley rats were used in the present study. TMP was administered by intravenous (i.v.) injection, and the Akt inhibitor MK2206 was injected intracerebroventricularly (i.c.v.). SAH grade, neurological scores, and brain water content were measured 24 h after SAH. Neuronal apoptosis was visualized by Fluoro-Jade C (FJC) staining. Western blotting was used to measure the levels of PERK, p-PERK, eIF2α, p-eIF2α, Akt, p-Akt, Bcl-2, Bax, and cleaved caspase-3. Our results showed that TMP effectively reduced neuronal apoptosis and improved neurobehavioral deficits 24 h after SAH. Administration of TMP reduced the abundance of p-PERK and p-eIF2α. In addition, TMP increased the p-Akt level and the Bcl-2/Bax ratio and decreased the level of cleaved caspase-3. The selective Akt inhibitor MK2206 abolished the anti-apoptotic effect of TMP at 24 h after SAH. Collectively, these results indicate that Akt-related anti-apoptosis through the PERK pathway is a major, potent mechanism of EBI. Further investigation of this pathway may provide a basis for the development of TMP as a clinical treatment.

Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats

“…Tetramethylpyrazine (TMP) is an alkaloid extracted from the roots of Ligusticum chuanxiong Hort (8), and has important biological actions, including anti-inflammatory, cardioprotective, antioxidant, immune-enhanced and neuroprotective effects (9,10). Moreover, TMP has been reported to exert a neuroprotective role in Parkinson's disease (11) and cerebral ischemia/reperfusion (12).…”

Live and let die: signaling AKTivation and UPRegulation dynamics in SARS-CoVs infection and cancer

“…Feedback regulation between AKT and UPR pathways emerges as a master control mechanism of cell decision-making in terms of survival or death, showing the remarkable flexibility of signaling pathways which can direct cells to opposing fates depending on the dynamics of their activation. Recent work confirms the relevance of the crosstalk between the AKT and the UPR pathways [ 185 – 190 ].…”

Safflower extract improves depression in mice by inhibiting the TLR4-NLRP3 inflammation signaling pathway

“…In clinical studies, it has been found that somatic and social stress can both activate the NF-κB signaling pathway in depressive patients. In animal studies, investigators also found that the activation of NF-κB signals induced by chronic stress contributes to depression-like behaviors and reduces the proliferation of neural stem cells in rodents (13). Since lipopolysaccharide (LPS) strongly stimulates the expression of IL-1β and the activation of NF-κB, these depression-related behaviors have also been found in animal models of acute depression induced by LPS (14).…”