The phenylpropanoid micronutrient chlorogenic acid improves clinical rating scores in rabbits following multiple infarct ischemic strokes: Synergism with tissue plasminogen activator

Abstract

The present study assessed whether chlorogenic acid (CGA), a phenylpropanoid molecule that has multiple mechanisms of action would be useful to attenuate behavioral deficits associated with embolic strokes using the rabbit small clot embolic stroke model (RSCEM). Quantal analysis for each treatment determines the quantity of microclots (mg) that produce neurologic dysfunction in 50% of a group of animals ( P 50), with intervention considered beneficial if it increases the P 50 compared to controls. CGA (50 mg/kg) injected 5 min post-embolization significantly increased behavioral function and the P 50 to 3.61 ± 0.52 mg ( n = 19) compared to 1.58 ± 0.15 mg ( n = 26) in controls. In addition, CGA also increased the P 50 to 2.57 ± 0.28 mg ( n = 18) when administered 1 h post-embolization, but was ineffective when given 3 h following embolization ( P 50 = 1.22 ± 0.24 mg, n = 18). For combination studies with the thrombolytic tissue plasminogen activator (tPA), we used tPA at a standard dose of 3.3 mg/kg, which significantly increased the P 50 to 2.89 ± 0.29 mg ( n = 17) when administered 1 h after embolization, but not 3 h after embolization ( P 50 = 1.54 ± 0.27 mg, n = 18). However, when tPA (3.3 mg/kg) was combined with CGA (50 mg/kg) and administered 3 h following embolization, there was a significant increase in behavioral function as evidenced by an increase in the P 50 value to 3.40 ± 0.76 mg ( n = 23). In conclusion, as a mono-therapy CGA effectively reduced behavioral deficits when given up to 1 h following embolic strokes in rabbits. Moreover, there was a synergistic effect of the combination of tPA with CGA when administered 3 h following embolization. The results show that the therapeutic window for a standard effective dose of tPA could be increased by administration of CGA, suggesting that it may be most useful as a co-therapy with a standard thrombolytic treatment regimen.