There is cumulative evidence that the
serine-threonine kinase Akt and its downstream nuclear
transcription factor CREB are involved in neuronal survival and protection. The Akt activates and phosphorylates CREB at Ser133, resulting in the up-regulation of pro-survival CREB target genes such as
BDNF and Bcl-2. Thus, Akt/CREB signaling pathway may be one propitious target for treatment of ischemic cerebral injury.
Nobiletin (NOB) exhibits a wide spectrum of beneficial
biological properties including anti-inflammatory,
antioxidant, anti-carcinogenic actions and contributes to reverse learning impairment in
Alzheimer's disease rat. However, little is currently known regarding the exact role of NOB in
ischemic stroke. Here, we designed to evaluate its possible
therapeutic effect on
cerebral ischemia. Adult male Sprague-Dawley rats were subjected to permanent
middle cerebral artery occlusion (pMCAO) and randomly divided into five groups:
Sham (
sham-operated+0.05%
Tween-80), MCAO (pMCAO+0.9% saline), Vehicle group (pMCAO+0.05%
Tween-80), NOB-L (pMCAO+NOB 10 mg/kg) and NOB-H (pMCAO+NOB 25 mg/kg) groups. Rats were pre-administered intraperitoneally once daily for 3 days before surgery and then received once again immediately after surgery. Neurological deficit scores, brain water content and
infarct volume were evaluated at 24 h after
stroke. Additionally, the activities of Akt, CREB,
BDNF, Bcl-2 and
claudin-5 in ischemic brain cortex were analyzed by the methods of immunohistochemistry, western blot and RT-qPCR. Compared with Vehicle group, neurological deficits and
brain edema were relieved in NOB-H group (P<0.05),
infarct volume was lessened in both NOB-L and NOB-H groups (P<0.05) at 24 h after
stroke. Immunohistochemistry, western blot and RT-qPCR analysis indicated that NOB dramatically promoted the activities of Akt, CREB,
BDNF and Bcl-2 (P<0.05). Meanwhile,
claudin-5 expression was also enhanced. On the basis of these findings, we concluded that NOB protected the brain from ischemic damage and it maybe through activating the Akt/CREB signaling pathway and ameliorating BBB permeability.