D-JNKi, a peptide inhibitor of c-Jun N-terminal kinase, promotes functional recovery after transient focal cerebral ischemia in rats.
The c-Jun-N-terminal kinase (JNK) pathway has been shown to play an important role in excitotoxic neuronal death and several studies have demonstrated a neuroprotective effect of D-JNKi, a peptide inhibitor of JNK, in various models of cerebral ischemia. We have now investigated the effect of D-JNKi in a model of transient focal cerebral ischemia (90 min) induced by middle cerebral artery occlusion (MCAo) in adult male rats. D-JNKi (0.1 mg/kg), significantly decreased the volume of infarct, 3 days after cerebral ischemia. Sensorimotor and cognitive deficits were then evaluated over a period of 6 or 10 days after ischemia and infarct volumes were measured after behavioral testing. In behavioral studies, D-JNKi improved the general state of the animals as demonstrated by the attenuation of body weight loss and improvement in neurological score, as compared with animals receiving the vehicle. Moreover, D-JNKi decreased sensorimotor deficits in the adhesive removal test and improved cognitive function in the object recognition test. In contrast, D-JNKi did not significantly affect the infarct volume at day 6 and at day 10. This study shows that D-JNKi can improve functional recovery after transient focal cerebral ischemia in the rat and therefore supports the use of this molecule as a potential therapy for stroke.
Esneault
E
E
Porsolt and Partners Pharmacology, ZA des Suhards, 53940 Le Genest Saint Isle, France. eesneault@porsolt.com
Castagne
V
V
Moser
P
P
Bonny
C
C
Bernaudin
M
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007839:Functional Laterality; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy*; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects*
D004791:Enzyme Inhibitors; C525168:L-JNKI-1; D018696:Neuroprotective Agents; D010455:Peptides; D016291:Dizocilpine Maleate