Drug Therapies for Stroke and Traumatic Brain Injury Often Display U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications

This article explores the occurrence of U-shaped dose responses induced by neuroprotective agents in animal stroke and traumatic brain injury (TBI) screening/preclinical studies. The assessment was stimulated by suggestions that U-shaped dose responses may be common for neuroprotective agents in stroke and TBI models, and its lack of both recognition and understanding may be a factor contributing to the failure of many promising drugs to be protective in clinical trials. Over 30 agents with neuroprotective properties in animal stroke/TBI models were identified that act via U-shaped dose responses in a broad range of experimental protocols. These findings suggest that U-shaped dose responses in animal stroke/TBI models may be a general occurrence and have significant implications for drug discovery, drug development, and clinical practice.