oxadiazoles and Brain-Injuries

Topics: Adolescent; Adult; Aged; Blood Pressure; Brain; Brain Injuries; Brain Neoplasms; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical Trials as Topic; Ethylamines; Evaluation Studies as Topic; Humans; Middle Aged; Oxadiazoles; Papaverine; Regression Analysis; Vasodilator Agents; Xenon

Appending lipophilic cations to small molecules has been widely used to produce mitochondria-targeted compounds with specific activities. In this work, we obtained a series of derivatives of the well-known fluorescent dye 7-nitrobenzo-2-oxa-1,3-diazole (NBD). According to the previous data [Denisov et al. (2014) Bioelectrochemistry, 98, 30-38], alkyl derivatives of NBD can uncouple isolated mitochondria at concentration of tens of micromoles despite a high pK

Topics: Animals; Anti-Bacterial Agents; Bacillus subtilis; Brain Injuries; Disease Models, Animal; Energy Metabolism; Mitochondria, Liver; Neuroprotective Agents; Nitrobenzenes; Organophosphorus Compounds; Oxadiazoles; Rats; Thermogenesis

In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.5 h after the insult. The number of apoptotic neurons in the immature rat brain was evaluated after 24 h. The wet weight of both hemispheres was determined 14 days after H-I, and its loss was used as an indicator of brain damage. In the vehicle-treated groups, H-I reduced the weight of the ipsilateral (ischemic) hemisphere by approximately 33% and sixfold increased the number of apoptotic cells in the cortex. Fenobam (10 mg/kg) and ADX47273 (5, 10, and 30 mg/kg) had no significant effect on brain damage, although application of fenobam at this dose significantly reduced the number of apoptotic cells. In contrast, fenobam (20 mg/kg) potentiated ischemic brain damage to 57.4% and had no effect on H-I-induced apoptosis. In all of the experimental groups, we detected no significant changes in the weight of the contralateral (control) hemisphere or the rectal temperature. In conclusion, in 7-day-old rats, the bidirectional modulation of mGluR5 by fenobam (10 mg/kg) and ADX47273 (all doses tested) did not result in significant changes in H-I-evoked brain damage, supporting our previous data indicating that also the antagonists of mGluR5 MPEP and MTEP, which reduce neuronal lesions in adult animals submitted to brain ischemia, were ineffective in 7-day-old rat pups.

Topics: Allosteric Regulation; Animals; Animals, Newborn; Brain Injuries; Female; Hypoxia-Ischemia, Brain; Imidazoles; Male; Neuroprotective Agents; Oxadiazoles; Piperidines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Treatment Outcome

We investigated the role of nitric oxide (NO) in the vascular response to high extraluminal K(+)-concentrations in the in vitro model of isolated rat middle cerebral arteries (MCA). Under control conditions, rat MCA dilated at 20, 30, 40 and 60 mM K(+). At 80 mM K(+), a slight vasoconstriction occurred. The unspecific NO synthase (NOS)-inhibitor L(omega)-nitro-L-arginine (L-NNA) increased the resting tone at 3 mM K(+) by 31+/-5% (P<0.01). While the vasodilatative effect of 20 mM K(+) was unaffected by L-NNA, NOS-inhibition resulted in vasoconstriction at > or = 40 mM K(+) (P<0.01). In presence of L-NNA, the basal vessel diameter was restored by either the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) or the cell-permeable guanosine-3',5'-cyclic monophosphate (cGMP) analogue 8-Br-cGMP. Co-application of L-NNA with either SNAP or 8-Br-cGMP resulted in partial restitution of the vasodilatative effect of 40 mM K(+), respectively. In presence of the soluble guanylyl cyclase inhibitor 1 H-[l,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), the vascular response to 40 mM K(+) was abolished. Our findings together with findings from the literature indicate a modulator role of NO at K(+) > or = 40 mM K(+), involving a cGMP-dependent mechanism.

Topics: Animals; Brain Injuries; Cerebrovascular Circulation; Cyclic GMP; Enzyme Inhibitors; Extracellular Space; Male; Middle Cerebral Artery; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Organ Culture Techniques; Oxadiazoles; Penicillamine; Potassium; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Vasodilation

Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed post-trauma survival periods of 5 min, 3 and 24 h. Regional glutamate receptor subtype binding was assessed with quantitative autoradiography in each group for N-methyl-D-aspartate (NMDA), quisqualate and kainate receptor subpopulations at approximately the -3.8 bregma level and compared to a sham control group. [3H]glutamate binding to the NMDA receptor was significantly (P less than 0.05) decreased at 3 h post-TBI in the hippocampal CA1 stratum radiatum, the molecular layers of the dentate gyri and the outer (layers 1-3) and inner (layers 5 and 6) overlying neocortex. NMDA receptor binding was significantly reduced in layers 5 and 6 of the neocortex at all post-trauma survival times but no further differences were seen in the hippocampi. No significant changes were observed with [3H]AMPA binding to quisqualate receptors and [3H]KA binding was significantly reduced only in layers 5 and 6 of the neocortex at 24 h after TBI. These data further confirm the pathological involvement of the NMDA receptor complex in brain regions selectively vulnerable to moderate levels of TBI in this model.

Topics: Animals; Brain Injuries; Kainic Acid; Oxadiazoles; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

[3H]Vesamicol binding was characterized in human brain post mortem. The number of binding sites was then determined in parallel with choline acetyltransferase activity in the temporal cortex of patients with Alzheimer's disease, demented and non-demented patients with Parkinson's disease, and in the cerebral cortex of rats with quisqualic acid lesions of the nucleus basalis magnocellularis. Whereas choline acetyltransferase activity decreased in patients with Alzheimer's or Parkinson's disease indicating loss of cholinergic innervation, the number of binding sites for [3H]vesamicol was the same as or higher than in controls. Similar results were obtained with the lesioned rats. It is suggested that the increase in binding sites may reflect compensatory regulation of the spared neurons at the level of the synaptic vesicle.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Brain Injuries; Choline O-Acetyltransferase; Female; Humans; Hydroxydopamines; Kinetics; Male; Neuromuscular Depolarizing Agents; Oxadiazoles; Oxidopamine; Parkinson Disease; Phencyclidine; Piperidines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine; Reference Values; Substantia Nigra; Temporal Lobe