c-Jun N-terminal kinase pathway inhibition in intracerebral hemorrhage

Abstract

Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH).

Methods: Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 microg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH.

Results: XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 +/- 11 vs. 39 +/- 5 mm(3) in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 +/- 13 vs. 26 +/- 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression.

Conclusions: XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The beneficial effects observed with XG-102 in ICH, as well as in ischemic stroke, open the possibility to rapidly treat stroke patients before imaging, thereby saving precious time.