betadex and Brain-Injuries

In our earlier work, a reduction of cholesterol content increased the extracellular glutamate level in rat brain nerve terminals (synaptosomes) that was a result of the lack of transporter-mediated glutamate uptake. The aim of this study was to assess transporter-mediated release of glutamate from cholesterol-deficient synaptosomes. In stroke, cerebral hypoxia/ischemia, and traumatic brain injury, the development of neurotoxicity is provoked by enhanced extracellular glutamate, which is released from nerve cells mainly by glutamate transporter reversal - a distinctive feature of these pathological states.. Laser scanning confocal microscopy, spectrofluorimetry, radiolabeled assay, and glutamate dehydrogenase assay.. Cholesterol acceptor methyl-β-cyclodextrin (15mM) reduced the cholesterol content in the synaptosomes by one quarter. Transporter-mediated glutamate release from synaptosomes: 1) stimulated by depolarization of the plasma membrane; 2) by means of heteroexchange with competitive transportable inhibitor of glutamate transporters dl-threo-β-hydroxyaspartate; 3) in low [Na(+)] medium; and 4) during dissipation of the proton gradient of synaptic vesicles by the protonophore cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP); was decreased under conditions of cholesterol deficiency by ~24, 28, 40, and 17%, respectively.. A decrease in the level of membrane cholesterol attenuated transporter-mediated glutamate release from nerve terminals. Therefore, lowering cholesterol may be used in neuroprotection in stroke, ischemia, and traumatic brain injury which are associated with an increase in glutamate uptake reversal. This data may explain the neuroprotective effects of statins in these pathological states and provide one of the mechanisms of their neuroprotective action. However, beside these disorders, lowering cholesterol may cause harmful consequences by decreasing glutamate uptake in nerve terminals.

Topics: Amino Acid Transport System X-AG; Animals; beta-Cyclodextrins; Brain; Brain Injuries; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Membrane; Cholesterol; Glutamic Acid; Hypoxia-Ischemia, Brain; Male; Membrane Potentials; Nerve Endings; Neuroprotective Agents; Protons; Rats; Rats, Wistar; Sodium; Stroke; Synaptic Vesicles; Synaptosomes

Systemic injections of the neurosteroid progesterone improve cognitive recovery after traumatic brain injury (TBI) and stroke, and decrease molecular indicators of neuronal damage. Suddenly withdrawing progesterone after repeated dosing (PW) exacerbates ischemia and causes increased anxiety, seizure susceptibility, and excitotoxicity. Adult male Sprague-Dawley rats received either bilateral medial frontal cortex contusions or sham surgery. Injections were administered at 1 and 6 h post-injury, then every 24 h for 7 days. Vehicle-treated rats received 2-hydroxypropyl-beta-cyclodextrin (HBC). Acute PW (AW) rats received a full 16 mg/ml of progesterone for 7 days, and tapered PW (TW) rats received 5 days at full dosage, then 2 days with progressively halved dosages. Anxiety behaviors were observed pre- and post-surgery, and compared to levels at the peak of withdrawal. AW rats with lesions exhibited significantly more anxiety than any other treatment group, while both lesion- and sham-operated TW rats were indistinguishable from vehicle-treated intact animals. After behavioral tests were complete, the brains were extracted and prepared for Western blotting. TNFalpha, cFos, Caspase-3, and NFkappaB, among others, were investigated. While all progesterone treatments resulted in improved molecular recovery, TW animals had significantly fewer active markers for apoptosis and inflammation than AW animals. In conclusion, although progesterone treatment decreases inflammation and apoptosis, acute withdrawal increases activity in some apoptotic and inflammatory pathways and increases anxiety behavior during the acute healing phase. A tapered withdrawal of the hormone further enhances short-term recovery after TBI.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Behavior, Animal; beta-Cyclodextrins; Blotting, Western; Brain Injuries; Caspase 3; Caspases; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Male; Maze Learning; NF-kappaB-Inducing Kinase; Progesterone; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Recovery of Function; Substance Withdrawal Syndrome; Time Factors; Tumor Necrosis Factor-alpha