Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits

Abstract

The therapeutic effects of atorvastatin on early brain injury (EBI), cerebral edema and its association with aquaporin 4 (AQP4) were studied in rabbits after subarachnoid hemorrhage (SAH) using western blot analysis and the dry-wet method. Seventy-two healthy male New Zealand rabbits weighing between 2.5 and 3.2 kg were randomly divided into three groups: the SAH group (n=24), sham-operated group (n=24) and the SAH + atorvastatin group (n=24). A double SAH model was employed. The sham-operated group were injected with the same dose of saline solution, the SAH + atorvastatin group received atorvastatin 20 mg/kg/day after SAH. All rabbit brain samples were taken at 72 h after the SAH model was established successfully. Brain edema was detected using the dry-wet method after experimental SAH was induced; AQP4 and caspase-3 expression was measured by western blot analysis, and neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining at 72 h after SAH. The results indicated that brain edema and injury appeared soon after SAH, while brain edema and EBI were ameliorated and increased behavior scores were noted after prophylactic use of atorvastatin. Compared with the SAH group, the level of AQP4 and the cerebral content of water was significantly decreased (P<0.01) by atorvastatin, and TUNEL staining and studying the expression of caspase-3 showed that the apoptosis of neurons was reduced markedly both in the hippocampus and brain cortex by atorvastatin. The results suggest that atorvastatin ameliorated brain edema and EBI after SAH, which was related to its inhibition of AQP4 expression. Our findings provide evidence that atorvastatin is an effective and well-tolerated approach for treating SAH in various clinical settings.

Protective effects of atorvastatin on cerebral vessel autoregulation in an experimental rabbit model of subarachnoid hemorrhage

“…The temperature of the feeding and operation rooms was maintained at 22°C. Atorvastatin (20 mg/kg/d; Pfizer, Inc., Wuxi, China) was administered by gastric gavage once daily for 3 days prior to SAH operation and 22 h post-SAH to maintain drug levels ( 14 ). Neurological deficits were assessed 24 h following SAH operation and rabbits were euthanized immediately following evaluation.…”

“…SAH was induced according to a previously described two-hemorrhage rabbit model ( 10 , 14 ). Briefly, rabbits were anesthetized with an auricular marginal vein injection of 10% chloral hydrate (2.5 ml/kg).…”

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

“…Single nucleotide polymorphisms (SNP) in the AQP-4 gene are associated with functional outcome, however have not been evaluated with regards to CE generation[1]. Although current therapies against CE are reactionary and non-specific (hyperosmolar treatment, neuromuscular blockade, cerebrospinal fluid (CSF) drainage, decompressive craniotomy), ongoing identification of causative pathways involved in CE has the potential to lead to the development of targeted treatment[7,10,12,13]. Genetic polymorphisms in these pathways could alter gene expression and regulation, as well as modify protein structure and function.…”

Aquaporin-4 and Cerebrovascular Diseases

“…Till now, studies in SAH models mainly focus on effects of AQP4 on early brain injury. AQP4 is increased at 6 h after SAH and maintains high levels within 72 h [97,98,99,100,101]. Moreover, one study indicates an increase of AQP4 at 7 days after SAH, which is located in the phase of delayed brain injury [102].…”