Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

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.

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

“…The well-known process of neuronal death, which begins in the first minutes after a traumatic brain injury, can potentially lead to an increase in the glutamate levels in cerebrospinal fluid (CSF) and extracellular fluid (ECF) of the brain to the levels of glutamate in the whole brain, up to 10,000–12,000 µM/kg [ 12 ]. However, in practice, such high levels of glutamate in CSF and ECF of the brain do not occur, and glutamate concentrations are usually limited to about 20–50 µM/L [ 46 , 47 , 48 , 49 , 50 ]. The explanation for this phenomenon is that even with the complete destruction of the BBB, concentrations of glutamate in the CSF and ECF of the brain cannot exceed the concentration of plasma glutamate, which is approximately 50–100 µM/L [ 12 ].…”

“…OxAc and pyruvate infusions reduce the severity of neurological deficits and symptoms of depression in rats after stroke [ 106 ] and traumatic injury in the brain [ 46 ]. The therapeutic effect of pyruvate on aggression and anxiety symptoms in a rat model of TBI has been observed in our laboratory (data yet to be published).…”

“…OxAC, pyruvate, GPT, and GOT have been proposed as treatments for TBI and stroke [ 46 , 106 , 108 , 109 , 110 ]. The safety of OxAc and pyruvate has been shown in elderly patients [ 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ], and its potential in alleviating symptoms of anxiety, depression, suicidal ideation, and aggression in women with PMS was suggested in a clinical trial [ 121 ].…”

Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System

“…As a whole, these data suggest that glutamate receptor abnormalities and changes in blood, plasma and brain glutamate levels are involved in the pathophysiology of MDD. Studies of depressive-like behavior in genetic models of deficient glutamate function and advances in the treatment of MDD with glutamate-based antidepressants strongly support this theory [ 30 , 31 , 32 ].…”

“…Studies report that a quarter to a half of sufferers develop major depression within the first year following TBI [ 82 , 83 ]. A rodent model of TBI used pyruvate as an effective treatment toward mitigating post-TBI depressive-like symptoms, proposing its viability for future studies in the topic of treatments for post-TBI depression in humans [ 31 ].…”