oligomycins and Brain-Injuries--Traumatic

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations. Synaptic mitochondria are reported to be more vulnerable to injury; however, this is the first study to characterize the temporal profile of synaptic and non-synaptic mitochondria following TBI, including investigation of respiratory dysfunction and oxidative damage to mitochondrial proteins between 3 and 120 h following injury. These results indicate that synaptic mitochondria are indeed the more vulnerable population, showing both more rapid and severe impairments than non-synaptic mitochondria. By 24 h, synaptic respiration is significantly impaired compared to synaptic sham, whereas non-synaptic respiration does not decline significantly until 48 h. Decreases in respiration are associated with increases in oxidative damage to synaptic and non-synaptic mitochondrial proteins at 48 h and 72 h, respectively. These results indicate that the therapeutic window for mitochondria-targeted pharmacological neuroprotectants to prevent respiratory dysfunction is shorter for the more vulnerable synaptic mitochondria than for the non-synaptic population.

Topics: Animals; Brain Injuries, Traumatic; Cell Respiration; Lipid Peroxidation; Male; Mitochondria; Oligomycins; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Synapses

Cerebral edema represents a major threat following traumatic brain injury. However, therapeutic measures for control of intracranial pressure alone have failed to restore cerebral metabolism and improve neurological outcome. Since mitochondrial damage results in ATP depletion and deactivation of membrane ionic pumps, we hypothesized that modulation of ATP bioavailability may directly affect cytotoxic edema. Intracranial pressure measurements were performed in Sprague-Dawley rats treated by intraperitoneal injection of dimethylsulfoxide (vehicle), cyclosporine A (CsA), or Oligomycin B (OligB) following cortical contusion and further correlated with water content, mitochondrial damage, and electron microscopic assessment of neuronal and axonal edema. As hypothesized, ultra-structural figures of edema closely correlated with intracranial pressure elevation, increased water content and mitochondrial membrane permeabilization expressed by loss of transmembrane mitochondrial potential. Further, mitochondrial damage evidenced ultra-structurally by figures of swollen mitochondria with severely distorted cristae correlated with both cytotoxic edema and mitochondrial dysfunction. Importantly, cerebral edema and mitochondrial impairment were significantly worsened by treatment with OligB, whereas a noticeable improvement could be observed in animals that received injections of CsA. Since OligB and CsA are responsible for symmetrical and opposite effects on oxidative metabolism, these findings support the hypothesis of a causative relationship between edema and mitochondrial function.

Topics: Animals; Brain Edema; Brain Injuries, Traumatic; Cyclosporine; Intracranial Pressure; Mitochondria; Mitochondrial Membranes; Oligomycins; Rats; Rats, Sprague-Dawley