Effect of long-term administration of JTP-2942, a novel thyrotropin-releasing hormone analogue, on neurological outcome, local cerebral blood flow and glucose utilization in a rat focal cerebral ischemia.
The effect of JTP-2942, a novel thyrotropin-releasing hormone analogue on neurological examination, local cerebral blood flow (l-CBF) and local cerebral glucose utilization (l-CGU) were examined when JTP-2942 was administered for 4 weeks after 1 week reperfusion following ischemia in a rat middle cerebral artery (MCA) occlusion. Left middle cerebral artery ischemia was induced for 90 min followed by reperfusion. JTP-2942 (0.03 or 0.003 mg/kg) or saline (vehicle) were administered for 4 weeks after 1 week ischemia, and then the drug was withdrawn. Neurological symptoms and motor disturbance based on inclined plane test were measured once a week after 1 week ischemia. l-CBF and l-CGU were measured by quantitative autoradiographic technique after 6 weeks ischemia. The adjacent sections subjected to l-CBF or l-CGU measurement were stained with Hematoxylin-Eosin, and the infarction volume was measured. JTP-2942 (0.03 mg/kg) significantly ameliorated neurological symptoms and motor disturbance at 5 weeks after ischemia as compared with vehicle, and then after completion of drug administration, amelioration effect continued. JTP-2942 (0.03 mg/kg) also significantly ameliorated the reduced l-CBF and l-CGU in the peri-infarcted areas such as the frontal cortex, motor cortex and medial caudate-putamen. No significant differences were noted in the infarction volume among MCA occlusion rats. This indicates that activating reduced metabolic turnover associated with synaptic connection changes or the activation of compensation mechanisms may result in improvement of neurological symptoms and motor disturbances. It is therefore expected that JTP-2942 may be a possible therapeutic agent for motor disturbance during the subacute or chronic cerebral infarction.