Effect of L-carnitine and Mildronate on Cognitive Recovery after Traumatic Brain Injury: Assessment of the Role of Mitochondrial Function, Angiogenesis, and Neuroinflammation
Veronika V. Nesterova, Dianna S. Adzhemian, Viktoria A. Gribovskaya, Polina I. Babenkova, Mikhail E. Ivanov, Daria T. Chursina, Sofya R. Kononova, Artem P. Gureev, Egor Yu Plotnikov, Denis N. SilachevIntroduction:
Traumatic brain injury (TBI) frequently results in persistent cognitive deficits driven by secondary mechanisms including mitochondrial dysfunction, oxidative stress, and neuroinflammation. We compared the effects of L-carnitine and mildronate on spatial memory recovery after TBI and investigated the underlying cellular mechanisms.
Methods:
Male C57BL/6 mice were subjected to controlled cortical impact TBI and assigned to naïve, sham, TBI+saline, TBI+mildronate (100 mg/kg/day), or TBI+L-carnitine groups. Spatial working memory was evaluated using the Morris water maze over 21 days. At 24 days post-injury, we measured cortical and hippocampal malondialdehyde (MDA), mtDNA integrity and copy number, expression of genes related to mitochondrial biogenesis, glucose metabolism, angiogenesis, and neuroinflammation, and performed blood cytology.
Results:
TBI induced significant memory deficits, elevated MDA, and reduced mtDNA copy number without increased damage. Mildronate, but not L-carnitine, significantly improved cognitive performance. Mildronate upregulated Tfam, Glut4, Cd34, and Eng while downregulating Gfap in the hippocampus. Both compounds decreased MDA and circulating cell-free mtDNA.
Discussion:
Mildronate’s superior neuroprotection appears to involve enhanced mitochondrial biogenesis, glucose transport, and angiogenesis, alongside suppression of astrogliosis. In contrast, L-carnitine showed limited cognitive benefit, possibly due to insufficient mitochondrial renewal and vascular repair.
Conclusion:
Mildronate exerts greater neuroprotective effects than L-carnitine after TBI, likely via coordinated restoration of mitochondrial quality control, glucose utilization, and vascular remodeling, offering a promising strategy to mitigate post-traumatic cognitive decline.