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

Dmitry Frank; Benjamin F Gruenbaum; Ilan Shelef; Vladislav Zvenigorodsky; Olena Severynovska; Ron Gal; Michael Dubilet; Alexander Zlotnik; Ora Kofman; Matthew Boyko

doi:10.3389/fnins.2022.832478

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

Front Neurosci. 2022 Feb 14:16:832478. doi: 10.3389/fnins.2022.832478. eCollection 2022.

Authors

Affiliations

¹ Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
² Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL, United States.
³ Department of Radiology, Soroka University Medical Center, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
⁴ Department of Physiology, Faculty of Biology, Ecology and Medicine, Dnepropetrovsk State University, Dnepropetrovsk, Ukraine.
⁵ Department of Psychology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva, Israel.

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.

Keywords: depression; glutamate scavenging; neuroprotection; pyruvate; traumatic brain injury.