N-Acetyl-l-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice

Nivedita Hegdekar,Chinmoy Sarkar,Marta M Lipinski

doi:10.1038/s41598-021-88693-8

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and long-term disability around the world. Even mild to moderate TBI can lead to lifelong neurological impairment due to acute and progressive neurodegeneration and neuroinflammation induced by the injury. Thus, the discovery of novel treatments which can be used as early therapeutic interventions following TBI is essential to restrict neuronal cell death and neuroinflammation. We demonstrate that orally administered N-acetyl-l-leucine (NALL) significantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinflammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice. Our data indicate that partial restoration of autophagy flux mediated by NALL may account for the positive effect of treatment in the injured mouse brain. Taken together, our study indicates that treatment with NALL would be expected to improve neurological function after injury by restricting cortical cell death and neuroinflammation. Therefore, NALL is a promising novel, neuroprotective drug candidate for the treatment of TBI.

Highlights

Traumatic brain injury (TBI) is a major cause of mortality and long-term disability around the world
While a slight decrease in body weight was detected among all TBI mice at days 1 and 3 after injury, they gradually regained the body weight and no appreciable differences in their body weight was observed at day 28 after TBI (Fig. 1c)
Body weight increased gradually in both vehicle and NALL fed sham mice over the course of study. These results clearly suggest that inclusion of NALL in chow does not negatively affect food intake or body weight in mice with or without TBI

Summary

Introduction

Traumatic brain injury (TBI) is a major cause of mortality and long-term disability around the world. In TBI, primary mechanical injury to the brain, for example due to a fall or a vehicle accident, triggers a cascade of secondary deleterious events that can propagate the injury and last anywhere from days to years following the original traumatic impact These include excitotoxicity, perturbation in calcium homeostasis, oxidative stress and activation of caspases and calpain, leading to acute and progressive neurodegeneration[5]. Promising clinical outcomes following racemic NAL treatment, including improved ataxic symptoms and stabilized disease progression, were observed among small cohort of NPC patients, correlating to the pharmacological action of the drug observed in animal s tudies[16,18,19] These reports led us to hypothesize that NAL may be useful in improving outcomes after TBI

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Results

Conclusion