RESUMEN
Acute intracranial hypertension (AIH) is a common and tricky symptom that inflicts upon patients after traumatic brain injury (TBI). A variety of clinical options have been applied for the management of AIH, such as physiotherapy, medication, surgery and combination therapy. Specifically, controlled decompression (CDC) alleviates the extent of brain injury and reduces the incidence of a series of post-TBI complications, thereby enhancing the prognosis of patients suffering from acute intracranial hypertension. The objective of the present project is to illuminate the potential molecular mechanism that underlies the neuroprotective effects of CDC in a rat model of traumatic epidural intracranial hypertension (TEIH). Herein, we observed the functional recovery, the degree of brain edema, the level of apoptosis, the expressions of neuronal cell autophagy-related signaling pathway proteins (including Akt, p-Akt, LC3 and Beclin-1) in rat TEIH model at 24 h post-surgery. The results showed in comparison with rapid decompression (RDC), CDC reduced the degree of brain edema, diminished the level of cellular apoptosis and enhanced neurological function, and whereas the neuroprotective effect of CDC could be reversed by rapamycin (Rap). The expressions of Beclin-1 and LC3 in CDC group were significantly lower than those of RDC group, and the expression levels of these two proteins were significantly elevated after the addition of Rap. The expression of p-Akt in CDC group was considerably enhanced than RDC group. After the addition of LY294002, a PI3K/Akt pathway inhibitor, p-Akt protein expression was reduced, and the neuroprotective effect of the rats was markedly inhibited. Taken together, our data demonstrate the superior neuroprotective effect of CDC with regard to alleviating early brain edema, improving the neurological status, suppressing apoptosis and inhibiting neuronal autophagy via triggering PI3K/Akt signaling pathway.
RESUMEN
Subarachnoid hemorrhage (SAH) occurs most commonly after rupture of an aneurysm, resulting in high disability and mortality due to the absence of effective therapy. Its subsequent stage, early brain injury (EBI), promotes the sustainable development of injury in the brain and ultimately leads to poor prognosis. As a new antiepileptic drug, the effect of perampanel on EBI after SAH is unknown. Pyroptosis, a process of inflammatory programmed cell death, has been confirmed in most studies to play a substantial role in aggravating SAH-post EBI. Similarly, oxidative stress is closely involved in neuronal pyroptosis and the pathophysiological mechanism of SAH-post EBI, leading to a devastating outcome for SAH patients. Nonetheless, no studies have been conducted to determine whether perampanel reduces pyroptosis and oxidative stress in the context of SAH-induced EBI. Rat SAH model via endovascular perforation was constructed in this study, to assess the neuroprotective effect of perampanel on SAH-post EBI, and to clarify the possible molecular mechanism. By means of the neurological score, brain edema detection, FJB staining, immunofluorescence, WB, ELISA, and ROS assay, we found that perampanel can improve neuroscores and reduce brain edema and neuronal degeneration at 24 h after SAH; we also found that perampanel reduced oxidative stress, neuronal pyroptosis, and inhibition of the SIRT3-FOXO3α pathway at 24 h after SAH. When 3-TYP, an inhibitor of SIRT3, was administered, the effects of perampanel on the SIRT3-FOXO3a pathway, antioxidant stress, and neuronal pyroptosis were reversed. Taken together, our data indicate that perampanel attenuates oxidative stress and pyroptosis following subarachnoid hemorrhage via the SIRT3/FOXO3α pathway. This study highlights the application value of perampanel in subarachnoid hemorrhage and lays a foundation for clinical research and later transformation of perampanel in SAH.