Characterization and Preclinical Treatment of Rotational Force-Induced Brain Injury

Abstract

Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks to months after injury and impede neurological recovery. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of rotational head trauma in rodents and extensively characterized the pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant cyclin dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. Finally, we utilize Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

Unveiling the Role of PSD95 Phosphorylation after Traumatic Brain Injury: Insights from Phosphoproteomic Analysis

“…Rida et al applied phosphoproteomics to explore the tyrosine-kinase signaling in TBI mouse, identifying Met/HGFR as a regulator in TBI neuroin ammatory responses [24]. Alan et al applied Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rotational TBI (rTBI) and found out the importance of Cdk5 in TBI pathophysiology [25]. Yutao et al detected TBI proteome and phosphoproteome of TBI mice and bioinformatics was used to reveal protein networks, while the study did not focus on some speci c pathways or proteins [26].…”