Carbonyl Scavenging as an Antioxidant Neuroprotective Strategy for Acute Traumatic Brain Injury

Introduction

Oxygen radical-induced membrane lipid peroxidation (LP) is a highly validated secondary injury mechanism that occurs following traumatic brain injury (TBI) that has been firmly established as a major contributor to multiple aspects of TBI pathophysiology due to oxidative damage to neural cell membrane lipids and proteins ( ). A major source of the posttraumatic free radicals that are generated come from leakage of the reactive nitrogen species (RNS) peroxynitrite anion (ONOO ⁻ ) which is generated by the diffusion rate-limited reaction of superoxide radicals (O ₂ ⁻ ) that are generated by a number of sources in the traumatized nervous tissue, and nitric oxide radicals ( NO) produced by both constitutive and inducible nitric oxide synthases. While LP can negatively impact many cellular functions, one of the main consequences of LP-mediated cellular damage is to disrupt mitochondrial functions including mitochondrial respiration/oxidative phosphorylation (ie, ATP generation), cause loss of membrane potential (Δ _Ψ ), and impairment of Ca ²⁺ uptake (ie, Ca ²⁺ buffering). This ultimately leads to mitochondrial permeability transition (MPT) and dumping of Ca ²⁺ into the cytoplasm. Collectively, these effects exacerbate intracellular Ca ²⁺ overload which leads to massive activation of calpains, proteolytic degradation of cytoskeletal and other proteins, and ultimately neurodegeneration schematically outlined in Fig. 13.1 .

TBI represents a major unmet medical need in that despite multiple efforts, no neuroprotective pharmacotherapy has yet been successfully developed to the point of earning FDA approval. Nevertheless, demonstration of neuroprotective effects of various compounds in experimental TBI models strongly suggests that effective clinical neuroprotection in TBI patients should be possible. In view of the nearly successful development of the LP inhibitor tirilazad at least for TBI patients who have traumatic subarachnoid hemorrhage (tSAH) ( ), as well as the repeated demonstration that LP inhibitors can improve neurological recovery and lessen neurodegeneration in rodent TBI paradigms ( ), inhibition of LP remains one of the more promising mechanistic approaches for trying to achieve clinical translation. Furthermore, the fact that much of the LP-related damage is due to the neurotoxic action of aldehydic end products such as 4-HNE and acrolein has offered up a new approach to antagonizing LP-related oxidative damage ( ).