4-hydroxy-2-nonenal and Brain-Edema

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in youth, but to date, effective therapies are still lacking. Previous studies revealed a marked response of apolipoprotein J (ApoJ) expression to the brain injury. The aim of this study was to determine the potential roles of ApoJ in functional recovery following TBI. After controlled cortex impact (CCI), a TBI model, in adult wild-type mice, ApoJ expression was up-regulated since 6 h post-injury and sustained for 5 days. Animals infused with recombinant human ApoJ intraventricularly at 30 min prior to CCI showed significantly reduced oxidative stress (3-nitrotyrosine, 4-hydroxynonenal) and complement activation (C5b-9). In addition, ApoJ treatment was shown to suppress the inflammatory response (glial activation, cytokine expression), blood-brain barrier disruption (Evans blue extravasation), and cerebral edema (water content) induced by CCI. Concomitantly, improved neuronal maintenance and neurological behavioral performance were observed in ApoJ-treated mice compared with the vehicle group. These findings support a neuroprotective role of ApoJ via multifunctional pathways, providing a novel and encouraging treatment strategy for TBI. Apolipoprotein J (ApoJ) was up-regulated after controlled cortical impact (CCI). Mice infused with human recombinant ApoJ prior to CCI showed reduced expression of complement and oxidative marker proteins as well as reduced inflammatory response and attenuated blood-brain barrier (BBB) disruption and cerebral edema. Neuronal maintenance and behavioral performance were improved by ApoJ infusion. These findings demonstrated the protective function of ApoJ for traumatic brain injury (TBI) therapy.

Topics: Aldehydes; Animals; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cerebral Cortex; Clusterin; Disease Models, Animal; Infusions, Intraventricular; Male; Mice, Inbred C57BL; Neuroprotective Agents; Tyrosine

This study aims to determine if erythromycin provides neuroprotective effects against ischemic injury following permanent focal cerebral ischemia.. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Each animal received a single subcutaneous injection of erythromycin lactobionate (EM, 50 mg/kg) or vehicle immediately after ischemia. The infarct volume, edema index and neurological performance were evaluated at 24 and 72 h after MCAO. The cerebral blood flow (CBF) was measured with an MRI system at 30 min after MCAO. TUNEL staining and immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) in the cortex were conducted at 24 and 72 h after MCAO.. The CBF did not differ between the EM-treated and vehicle-treated groups. The EM treatment significantly reduced the infarct volume (p < 0.01) at 24 and 72 h after MCAO and significantly reduced the edema index (p < 0.01) at 24 h. The EM treatment significantly improved the neurological deficit scores (p < 0.05) at 24 and 72 h. EM also significantly suppressed the accumulation of 4-HNE (p < 0.01) and 8-OHdG (p < 0.01) and markedly reduced Iba-1 (p < 0.01) and TNF-α expression (p < 0.05) at both time points. The EM treatment significantly reduced TUNEL-positive cells (p < 0.01) at both time points.. These findings suggest that EM can protect against the neuronal damage caused by cerebral ischemia by alleviating inflammation and reducing oxidant stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Blood Pressure; Body Temperature; Brain Edema; Brain Infarction; Brain Injuries; Calcium-Binding Proteins; Cerebrovascular Circulation; Deoxyguanosine; Disease Models, Animal; Erythromycin; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Microfilament Proteins; Neuroprotective Agents; Rats; Statistics, Nonparametric; Time Factors; Tumor Necrosis Factor-alpha

Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2'-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment after TBI was only observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Brain Edema; Brain Injuries; Catechin; Deoxyguanosine; Disease Models, Animal; DNA, Single-Stranded; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Lipid Peroxidation; Male; Maze Learning; Neurons; Neuroprotective Agents; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Time Factors

The hypertensive rat brain exhibited softening, severe edema and intracerebral hemorrhage. The NO(2) (-) + NO(3) (-) (NOx) level in the hypertensive rat brain was higher than in the normotensive rat brain. Light microscopy demonstrated severe arterial and arteriolar lesions with fibrinoid deposits and medial lesion. After injecting hypertensive rats with nitroblue tetrazolium (NBT), formazan deposits, which are the reaction product of reduction of NBT by superoxide, were observed in the microvessels and nervous tissue around the microvessels of injured brain. Immunohistochemistry showed that copper zinc superoxide dismutase and manganese superoxide dismutase expression of the endothelial cells of hypertensive rats were also upregulated in comparison with normotensive rat endothelial cells. Inducible nitric oxide synthase and endothelial nitric oxide synthase expression in endothelial cells of normotensive rats were strongly positive, whereas the expression in hypertensive rat endothelial cells was weaker. Nitrotyrosine, a biomarker of peroxynitrite, which is a powerful oxidant formed by the reaction of nitric oxide (NO) with superoxide, was found in the microvessels, injured arteries and arterioles and infarcted brain tissue. Deposition of a major aldehydic product of lipid peroxidation, that is, 4-hydroxy-2-nonenal (4-HNE) was found in microvessels, perivascular tissue, and edematous and infarcted brain. Hypertensive cerebrovascular disease is the result of hypertension-induced oxidative stress.

Topics: Aldehydes; Animals; Arterioles; Brain; Brain Edema; Cerebral Hemorrhage; Cerebrovascular Disorders; Disease Models, Animal; Endothelium, Vascular; Hypertension; Intracranial Arterial Diseases; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroblue Tetrazolium; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Tyrosine; Up-Regulation