Research ReportActivated autophagy pathway in experimental subarachnoid hemorrhage
Introduction
Subarachnoid hemorrhage (SAH) is a devastating disease causing high morbidity and mortality especially within the first few days (Broderick et al., 1994). Many survivors of SAH experience persistent cognitive deficits, with an effect on functional status and quality of life (Hütter et al., 2001). Although considerable advances have been made in endovascular techniques, diagnostic methods, and surgical and perioperative management paradigms, outcome for patients with SAH still remains poor (Bederson et al., 2009). Recently, the term “early brain injury” has been generated referring to the immediate injury within 72 h and includes secondary events to SAH before the development of cerebral vasospasm (Kusaka et al., 2004). The identification of the mechanisms underlying brain injury during this acute period has received much less attention than delayed cerebral vasospasm and therefore, therapeutic options are generally limited (Cahill et al., 2006).
Apoptosis has been reported to be involved in acute brain injury after experimental SAH and might explain the serious impact of this disease on short- as well as long-term outcomes (Matz et al., 2000, Sabri et al., 2008). More recently, increased autophagic changes in neuro-glial cells have been demonstrated in several experimental settings of acute brain injury (Carloni et al., 2008, He et al., 2008, Liu et al., 2008). However, the occurrence of autophagy in SAH has not been examined. Although, autophagy is a physiological process with removal of long-lived proteins and organelles through an autophagosomal–lysosomal pathway that is essential for cell homeostasis and survival, it can promote cell death (Wang and Klionsky, 2003). Therefore, its function in acute pathologic diseases of brain is unclear and there is controversy over whether activated autophagic pathway represents a mechanism of cell death or may be a rescue mechanism activated after injury as part of an endogenous neuroprotective response (Carloni et al., 2008).
Due to similarities in pathophysiological changes to those found with aneurysmal rupture in human, the endovascular perforation SAH rat model is considered most suitable for studying early brain injury following SAH (Bederson et al., 1995, Lee et al., 2009). In this study, a modified endovascular perforation technique was employed for SAH induction in the rat to investigate whether autophagic pathway is activated in early brain injury following SAH.
Section snippets
Physiological variables
Physiological data were measured before SAH induction. The mean values of blood pH, blood gases, mean arterial blood pressure, hematocrit, and blood glucose were controlled in normal ranges (MABP, 80–120 mm Hg; pO2, 80–120 mm Hg; pCO2, 35–45 mm Hg; hematocrit, 38–43%; blood glucose, 80–120 mg/dL).
SAH extent and mortality
None of the sham-operated control animals died or had any evidence of SAH. The mortality rate in SAH rats was 27% (n = 14 of 52). The deaths occurred within 3 h (n = 6) or between 6 and 24 h (n = 8)
Early brain injury following SAH
Early brain injury represents the primary cause of mortality and morbidity in SAH patients (Broderick et al., 1994, Bederson et al., 2009). It has been suggested that sudden rise in intracranial pressure and fall in cerebral blood flow leading to cerebral ischemia may play an important role. However, the exact underlying injury mechanisms during this early period following SAH have not been fully identified (Cahill et al., 2006).
Brain edema represents a major component of early brain injury
Animals
The protocols for these animal studies were approved by the University of Michigan Committee on the Use and Care of Animals at the University of Michigan.
A total of 70 adult male Sprague–Dawley rats weighing between 275 and 325 g was used in this study. Tissue samples were taken at 6, 24 and 72 h following SAH induction for analysis. Sham-operated animals were sacrificed 24 h after surgery. Five animals were required for brain water content, Western blot analysis and immunohistology. Three
Acknowledgments
This study was supported by the Else Kröner-Fresenius-Stiftung, Bad Homburg, Germany and German Society of Neurosurgery.
References (27)
- et al.
Anion-exchange blocker enhances cytoplasmic vacuole formation and cell death in serum-deprived mouse kidney epithelial cells in mice
Cell Biol. Int.
(2006) - et al.
Protective role of autophagy in neonatal hypoxia–ischemia induced brain injury
Neurobiol. Dis.
(2008) - et al.
Spinal cord injury induces upregulation of Beclin 1 and promotes autophagic cell death
Neurobiol. Dis.
(2009) - et al.
Subarachnoid hemolysate produces DNA fragmentation in a pattern similar to apoptosis in mouse brain
Brain Res.
(2000) - et al.
Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: a possible cause for poor prognosis
Brain Res.
(2008) - et al.
A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model
J. Neurosci. Methods
(2008) - et al.
Guidelines for the management of aneurismal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association
Stroke
(2009) - et al.
Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat
Stroke
(1995) - et al.
Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage
Stroke
(1994) - et al.
Mechanisms of early brain injury after subarachnoid hemorrhage
J. Cereb. Blood Flow Metab.
(2006)
Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome
Stroke
Closed head injury induces upregulation of Beclin 1 at the cortical site of injury
J. Neurotrauma.
Neurodegeneration induces upregulation of Beclin 1
Autophagy
Cited by (90)
Melatonin alleviates early brain injury by inhibiting the NRF2-mediated ferroptosis pathway after subarachnoid hemorrhage
2023, Free Radical Biology and MedicineRole of autophagy and transcriptome regulation in acute brain injury
2022, Experimental NeurologyFGF-2 suppresses neuronal autophagy by regulating the PI3K/Akt pathway in subarachnoid hemorrhage
2021, Brain Research BulletinDihydrolipoic acid enhances autophagy and alleviates neurological deficits after subarachnoid hemorrhage in rats
2021, Experimental Neurology