Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage

Abstract

Delayed cerebral ischemia (DCI) is a common and feared complication after subarachnoid hemorrhage (SAH), which occurs in approximately one third of patients. 1 The mechanisms that are involved in DCI development are largely unknown. Spreading depolarizations (SDs) have been suggested to be associated with DCI in experimental and clinical SAH studies. 2 SDs are waves of depolarizations of neurons and glial cells that spread across brain tissue at a speed of 2 to 6 mm/min. 3 SD is the underlying mechanism of a migraine aura, but may also be associated with other brain diseases. In migraine aura, the tissue recovers from the electrolyte imbalance caused by SDs, presumably through temporary hyperperfusion. 4 However, after an acute ischemic brain insult, such as SAH, SDs may cause permanent tissue injury arising from spreading ischemia because of an inverse hemodynamic response to SD combined with an increased metabolic demand. 2,5 In a small study of SAH patients who needed surgery for their ruptured aneurysm, SDs were recorded by electrocorticography and seemed associated with the development of DCI.5 Inhibition of SD is, therefore, a potential therapeutic approach to prevent brain injury after SAH.Multiple drugs, including antiepileptic drugs and migraine prophylactics, have SD-inhibiting properties. 6 For SAH patients, nimodipine is the only established drug for the clinical prevention of DCI.1 Although the mechanism of action Background and Purpose-Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction. Methods-Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T 2 -weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test. Results-In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproateand vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04 9-11 Intraperitoneal injection of valproate was found to decrease lesion size after ischemic stroke in a rat model, 12 where SDs have been shown to contribute to lesion growth. 13,14 Valproate treatment has also been shown to improve the outcome in a mouse model with SAH induced by subarachnoid blood injection.15 However, the mechanisms through which valproate may reduce b...

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“…The blood leaking into the subarachnoid space following SAH has the potential to cause severe brain edema and subsequent neurological deficits [35,36]. In addition, the toxic agents resulting from the breakdown of the blood cells cause further neural death, leading to permanent neurological deficits, including cognition, memory and learning disabilities [37]. In this study, we found that BMS-470539 treatment significantly alleviated neurological deficits and reduced brain edema at 24 h after SAH.…”

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice

“…200 mg/kg VPA is known to exert neuroprotective effects by reducing hippocampal neuron loss and improving cognitive function after cerebral ischemia in rats [ 33 ]. A previous study showed that the treatment of VPA (300 mg/kg) significantly reduced the growth of brain lesions with respect to delayed cerebral ischemia after subarachnoid hemorrhage [ 34 ]. Hemorrhage volume is a key factor related to most accepted predictors of ICH prognosis [ 35 ].…”

“…Nevertheless, the present study has some limitations. VPA may exert a variety of protective effects through various signaling pathways in the central nervous system [ 34 , 36 ]. In the present study, we only pay attention to the effect of VPA on BBB.…”

Acute mitogen‐activated protein kinase 1/2 inhibition improves functional recovery and vascular changes after ischaemic stroke in rat‐monitored by 9.4 T magnetic resonance imaging

“…The imaging was performed accordingly to previously described protocols . Although pre‐clinical rodent brain MRI at 9.4T can be acquired with 1‐mm slice thickness for high‐resolution morphological analysis, it was deemed appropriate to choose a slice thickness of 2 mm in this study considering that this is a common choice of spatial resolution for perfusion MRI investigations …”