Abstract
Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.
Highlights
The majority of survivors of moderate and severe traumatic brain injury (TBI) suffer from chronic neuropsychiatric consequences, including cognitive defects, depression, anxiety, social withdrawal and aggression (Tateno et al, 2003; McAllister, 2008; Jorge and Arciniegas, 2014; Hicks et al, 2019; Rauen et al, 2020)
We investigated blood glutamate scavenging activity from pyruvate administration and its mechanisms as a viable option for antidepressant treatment in a rat model of post-traumatic depression
Our results determined that pyruvate likely has an antidepressant effect on the brain via its participation in blood glutamate scavenging
Summary
The majority of survivors of moderate and severe traumatic brain injury (TBI) suffer from chronic neuropsychiatric consequences, including cognitive defects, depression, anxiety, social withdrawal and aggression (Tateno et al, 2003; McAllister, 2008; Jorge and Arciniegas, 2014; Hicks et al, 2019; Rauen et al, 2020) While these behavioral sequelae may at first be attributable to the emotional burdens of physical disability, these symptoms are not correlated with the severity of the initial injury or with pain (Bodnar et al, 2019) and can persist for decades (Hoofien et al, 2001; Koponen et al, 2002). As post-TBI depression remains difficult to manage, novel therapeutic approaches that target this and related neuropsychiatric conditions have been of great clinical interest
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