PP.29.16] NITROSONIFEDIPINE, A NOVEL ANTIOXIDANT, AMELIORATES NEUROLOGICAL SYMPTOMS AND PROLONGS THE SURVIVAL IN A MALIGNANT STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

Objective: Nitrosonifedipine (NO-NIF) is photolytic metabolite of nifedipine, an anti-hypertensive drug. We have revealed that NO-NIF possesses potent radical scavenging activity and protective effects against several pathological conditions involving oxidative stress. A malignant stroke-prone spontaneously hypertensive rat (M-SHRSP) is a model animal showing high rate of cerebral stroke. The onset and progressions of stroke are known to be involved in oxidative stress. Therefore, we investigated the effects of NO-NIF on the onset and progressions of stroke in M-SHRSP. Design and method: M-SHRSPs were treated with NO-NIF (30 mg/kg/day, i.p.) or vehicle from the age of five weeks. Neurological symptoms were observed every day and scored by severity of general status and disordered motility of anterior/posterior limbs. The day of the stroke onset was determined by neurological symptoms and the change in body weight. Brain was harvested after death and histologically analyzed. For in vitro study, nerve growth factor (NGF)-induced neurite elongation and intracellular signaling pathway were investigated using PC12 cells. Results: There was no significant difference in the incidence and the timing of stroke onset between control and NO-NIF treated group. However, the periods until 50% rats died from stroke were extended for 29 days in NO-NIF group compared to control. Although the neurological score showed linear worsening after stroke onset, NO-NIF significantly suppressed its exacerbation. Consistently, rats showed less pathological lesion, such as hemorrhage, thrombus, and liquefaction degeneration in brains. In PC12 cells, NGF-induced neurite elongation was enhanced by NO-NIF existence. Moreover, NO-NIF prolonged the co-localization of NGF receptor and flotillin, a lipid raft marker, and the activations of Akt and ERK1/2. In our previous study, we have already showed that NO-NIF affects the fluidity of cellular membrane. Therefore, it was considered that NO-NIF enhanced NGF signaling by changing the cellular membrane fluidity and localization of NGF receptor. Conclusions: In the present study, we demonstrated that NO-NIF could prolong the lifespan after stroke induced by malignant hypertension. NO-NIF were suggested to elongate neurite by enhancing NGF-stimulated intracellular signaling activities and finally improved the stroke-related neurological symptoms in M-SHRSP.