NADPH oxidases in traumatic brain injury – Promising therapeutic targets?

Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Despite intense investigation, no neuroprotective agents for TBI have yet translated to the clinic. Recent efforts have focused on identifying potential therapeutic targets that underlie the secondary TBI pathology that evolves minutes to years following the initial injury. Oxidative stress is a key player in this complex cascade of secondary injury mechanisms and prominently contributes to neurodegeneration and neuroinflammation. NADPH oxidase (NOX) is a family of enzymes whose unique function is to produce reactive oxygen species (ROS). Human post-mortem and animal studies have identified elevated NOX2 and NOX4 levels in the injured brain, suggesting that these two NOXs are involved in the pathogenesis of TBI. In support of this, NOX2 and NOX4 deletion studies have collectively revealed that targeting NOX enzymes can reduce oxidative stress, attenuate neuroinflammation, promote neuronal survival, and improve functional outcomes following TBI. In addition, NOX inhibitor studies have confirmed these findings and demonstrated an extended critical window of efficacious TBI treatment. Finally, the translational potential, caveats, and future directions of the field are highlighted and discussed throughout the review.

Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

“…Traumatic brain injury (TBI) and cerebral infarction cause the rapid activation of microglia [22]. The responses of microglia in TBI and cerebral infarction are characterized by morphological differentiation [23][24][25], migration [26], and phagocytosis [27], as well as the release of bioactive substances, such as cytokines/chemokines [28], ROS [29,30], and neuroprotective factors [25]. Whether microglia in severely injured brains are neurotoxic or neuroprotective is a matter of debate.…”

“…Oxidative stress caused by ROS in the acute phase of TBI and cerebral infarction is thought to be detrimental, and macrophages and microglia have been recognized as the main cells that produce ROS [29]. Cells contain various sources of ROS.…”

“…Cells contain various sources of ROS. NOX are well known as enzymatic systems that actively generate ROS [29]. The neurotoxicity of NOX-derived ROS is evident because knockout or inhibition of the NOX gene or its activities reduced the damaged area and improved neurological prognoses in models of TBI and cerebral infarction [65][66][67].…”

Nanosized carbon black exposure induces neural injury: effects on nicotinamide adenine dinucleotide phosphate oxidases and endoplasmic reticulum stress

“…As the enzyme family NOXs is one of the primary generators of ROS (Ma, Wang, Dhandapani, Wang, & Brann, ), it is reasonable to examine the expression of NOXs after the treatment of Printex 90. In line with the ROS generation aforementioned, Printex 90 treatment (above 6 μg/cm 2 ) significantly increased the expression of NOX2 and NOX4, with the peak response at 60 μg/cm 2 (Figure A and 4B), confirming that NOX2 and NOX4 participated in the Printex 90‐induced ROS generation.…”

“…A major source of ROS in injured nervous systems is the NOXs (Cooney, Bermudez‐Sabogal, & Byrnes, ). There are seven isotypes of the catalytic NOX subunits; of note, the NOX2 appears to be the dominant source of pathological oxidative stress mediated by specific stimulation, while other NOX isoforms might also be potential targets for brain injury, such as NOX4 (Ma et al, ; Nayernia, Jaquet, & Krause, ). In a subarachnoid haemorrhage model, the levels of NOX2 and NOX4 were substantially increased, and NOX2‐ and NOX4‐mediated neurotoxicity was further verified by an in vitro study.…”