Combining insulin-like growth factor derivatives plus caffeinol produces robust neuroprotection after stroke in rats

Abstract

Background and purpose: Insulin-like growth factor-1 (IGF-1) and caffeinol are both neuroprotective and probably have different mechanisms of action; therefore, they may be more effective in combination.

Methods: We tested the N-terminal tripeptide of IGF-1, Gly-Pro-Glu (GPE), and its analogue, G2MePE, alone and with caffeinol in a rat middle cerebral artery (MCA) suture occlusion model. We randomly assigned rats to 6 groups of 8 to 12 animals: (1) control; (2) GPE, 3 mg/kg per hour; (3) G2MePE, 0.3 mg/kg per hour; (4) caffeinol, a mixture of caffeine (10 mg/kg) with ethanol (0.32 g/kg); (5) GPE with caffeinol (combination of group 2 with 4); and (6) G2MePE with caffeinol (combination of group 3 with 4). Drugs were started 75 minutes after suture occlusion, at the start of reperfusion. Three days after MCA occlusion, neurological deficit (Neurological Deficit Score [NDS]) and lesion volume were measured.

Results: GPE and caffeinol improved NDS by 34% and 36%, respectively (P<0.01), and also decreased cortical but not striatal lesion volume compared with control (GPE cortex, 121 mm3; caffeinol cortex, 134 mm3; and control, 221 mm3; P<0.01). GPE plus caffeinol did not have more efficacy than either GPE or caffeinol alone. G2MePE slightly improved NDS (19.7%, P=0.05) but not lesion volume. However, G2MePE plus caffeinol very significantly improved NDS (64%) and lesion volume in both cortex (combination 95 mm3 versus control 221 mm3) and striatum (combination 74 mm3 versus control 110 mm3) (P<0.001), and was significantly more effective than either caffeinol or G2MePE alone.

Conclusions: Both GPE and caffeinol significantly protect cortex after MCA occlusion. At the doses used in this study, the GPE analogue G2MePE by itself had minimal protective effects, but when combined with caffeinol, it demonstrated robust beneficial effects on cortical and subcortical lesion size and behavioral deficit. Further study of this combination appears justified.