Traumatic brain injury heterogeneity affects cell death and autophagy.
Brandon Z McDonaldAria W TarudjiHaipeng ZhangSangjin RyuKent M EskridgeForrest M KievitPublished in: Experimental brain research (2024)
Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.
Keyphrases
- traumatic brain injury
- cell death
- neuropathic pain
- oxidative stress
- endoplasmic reticulum stress
- severe traumatic brain injury
- cell cycle arrest
- signaling pathway
- mild traumatic brain injury
- functional connectivity
- spinal cord
- drug induced
- spinal cord injury
- single cell
- mental health
- machine learning
- diabetic rats
- hepatitis b virus
- liver failure
- single molecule
- risk assessment
- acute respiratory distress syndrome
- optic nerve
- pi k akt