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 n eurological examination, local cerebral blood flow (1-CBF) and local cerebr al glucose utilization (1-CGU) were examined when JTP-2942 was administered for 4 weeks after 1 week reperfusion following ischemia in a rat middle ce rebral artery (MCA) occlusion. Left middle cerebral artery ischemia was ind uced 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(0.03 or 0.003 mg/kg) or saline (vehicle) were administered for 4 weeks after 1 week ischemia, and t hen the drug was withdrawn. Neurological symptoms and motor disturbance bas ed on inclined plane test were measured once a week after 1 week ischemia. I-CBF and 1-CGU were measured by quantitative autoradiographic technique af ter 6 weeks ischemia. The adjacent sections subjected to 1-CBF or 1-CGU mea surement were stained with Hematoxylin-Eosin, and the infarction volume was measured. JTP-2942 (0.03 mg/kg) significantly ameliorated neurological sym ptoms and motor disturbance at 5 weeks after ischemia as compared with vehi cle, and then after completion of drug administration, amelioration effect continued. JTP-2942 (0.03 mg/kg) also significantly ameliorated the reduced 1-CBF and 1-CGU in the peri-infarcted areas such as the frontal cortex. mo tor cortex and medial caudate-putamen. No significant differences were note d in the infarction volume among MCA occlusion rats. This indicates that ac tivating reduced metabolic turnover associated with synaptic connection cha nges 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 du ring the subacute or chronic cerebral infarction. (C) 2001 Elsevier Science B.V. All rights reserved.