alpha 7 Nicotinic Acetylcholine Receptor Agonist PNU-282987 Attenuates Early Brain Injury in a Perforation Model of Subarachnoid Hemorrhage in Rats

作者：Duris Kamil; Manaenko Anatol; Suzuki Hidenori; Rolland William B; Krafft Paul R; Zhang John H^*

来源：Stroke, 2011, 42(12): 3530-3536.

DOI：10.1161/STROKEAHA.111.619965

• alpha 7 nicotinic acetylcholine receptor
• PNU-282987
• subarachnoid hemorrhage
• early brain injury
• apoptosis
• Akt
• cleaved caspase 3

Background and Purpose-Early brain injury is an important pathological process after subarachnoid hemorrhage (SAH). The goal of this study was to evaluate whether the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) agonist PNU-282987 attenuates early brain injury after SAH and whether alpha 7nAChR stimulation is associated with down-regulation of caspase activity via phosphatidylinositol 3-kinase-Akt signaling.
Methods-The perforation model of SAH was performed, and neurological score, body weight loss, and brain water content were evaluated 24 and 72 hours after surgery. Western blot and immunohistochemistry were used for quantification and localization of phosphorylated Akt and cleaved caspase 3. Neuronal cell death was quantified with TUNEL staining. alpha 7nAChR antagonist methylcaconitine and phosphatidylinositol 3-kinase inhibitor wortmannin were used to manipulate the proposed pathway, and results were quantified with Western blot.
Results-PNU-282987 improved neurological deficits both 24 and 72 hours after surgery and reduced brain water content in left hemispheres 24 hours after surgery. PNU-282987 significantly increased phosphorylated Akt levels and significantly decreased cleaved caspase 3 levels in ipsilateral hemispheres after SAH. Methylcaconitine and wortmannin reversed effects of treatment. Phosphorylated Akt and cleaved caspase 3 were colocalized to neurons in the ipsilateral basal cortex. Phosphorylated Akt was mainly localized in TUNEL-negative cells. PNU-282987 significantly reduced neuronal cell death in the ipsilateral basal cortex.
Conclusions-alpha 7nAChR stimulation decreased neuronal cell death and brain edema and improved neurological status in a rat perforation model of SAH. alpha 7nAChR stimulation is associated with increasing phosphorylation of Akt and decreasing cleaved caspase 3 levels in neurons. (Stroke. 2011;42:3530-3536.)

• 出版日期2011-12