L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Traumatic brain injuries (TBIs) cause secondary damage through mitochondrial dysfunction.
• Mitochondrial DNA (mtDNA) damage, disrupted angiogenesis, and inflammation are key secondary injury mechanisms.
• Craniotomy and direct brain impact induce distinct molecular changes, including mtDNA depletion and glial activation.

Purpose of the Study:

• To investigate the therapeutic potential of L-carnitine and mildronate in mitigating secondary injury following TBI.
• To elucidate the effects of these agents on mitochondrial integrity, angiogenesis, and inflammation.
• To understand the opposing metabolic actions of L-carnitine and mildronate in the context of TBI.

Main Methods:

• Experimental induction of TBI in mice.
• Administration of L-carnitine and mildronate as potential therapeutic agents.
• Analysis of mitochondrial DNA copy number, gene expression related to angiogenesis, and inflammatory markers.
• Assessment of glial activation and gut microbiome composition.

Main Results:

• L-carnitine protected against mtDNA depletion by promoting mitochondrial biogenesis but exacerbated inflammation, potentially via gut microbiome alterations.
• Mildronate enhanced angiogenesis-related gene expression and reduced both local and systemic inflammation.
• Craniotomy alone induced mtDNA damage and inflammation, while direct impact led to mtDNA copy number reduction and glial activation.

Conclusions:

• Both L-carnitine and mildronate demonstrate potential for treating TBI-induced secondary injuries.
• L-carnitine's benefits in mitochondrial protection are counterbalanced by inflammatory effects.
• Mildronate offers a dual benefit of promoting angiogenesis and reducing inflammation, making it a promising therapeutic candidate.