Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury

• Published in: Experimental neurology 2024-12, Vol.382, p.114993, Article 114993
• Main Authors: Kalimullina, Tamila, Sachdeva, Rahul, Pawar, Kiran, Cao, Steven, Marwaha, Arshdeep, Liu, Jie, Plunet, Ward, Squair, Jordan, West, Christopher R., Tetzlaff, Wolfram, Krassioukov, Andrei V.
• Format: Article
• Language: English
• Subjects: Autonomic dysreflexia; Fluoxetine; Glyburide; Indomethacin; Neuroprotection; Spinal cord injury; Valproic acid
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2024.114993

Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI. Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed. Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2–3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]. Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations. •Study tested neuroprotective agents for cardiovascular recovery post-spinal cord injury.•No improvement was observed in cardiovascular function or motor recovery.•Indomethacin and Valproic acid caused high mortality despite doses deemed safe in literature.•Study emphasizes the need for re