Biomedical subjects

S F Ali

Publications and source records attributed to S F Ali.

201 records · Page 12Linked to original sources

PubMedDate not supplied

Effects of manganese on inositol polyphosphate receptors and nitric oxide synthase activity in rat brain.

The neurotoxic effects of excessive exposure to manganese (Mn) include degeneration of dopaminergic neurons, impairment of energy metabolism, and perturbations in phosphoinositide (PI) hydrolysis leading to altered calcium (Ca2+) homeostasis. This study is designed to assess the in vitro and in vivo effects of Mn on Ca2+/calmodulin-dependent neuronal nitric oxide synthase (nNOS) activity and on the regulation of inositol 1,4,5-trisphosphate (InsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4) receptors involved in intracellular and extracellular mobilization of Ca2+. In vivo Mn exposure significantly increased 3H-InsP3 and 3H-InsP4 binding in the cerebellum and the cerebral cortex in a dose-dependent manner. However, in vitro Mn decreased 3H-InsP3 binding and increased 3H-InsP4 binding. In vitro and in vivo exposure of Mn inhibited nNOS activity in the cerebellum and the cerebral cortex. Immunohistochemical studies also showed a notable decrease in nNOS immunoreactivity in the granule cell layer of the cerebellum, whereas no significant changes were observed in the cerebral cortex. These data suggest that Mn neurotoxicity may be due to altered calcium homeostasis by its modulation of inositol polyphosphate receptors. Further, the inhibition of nNOS by Mn is of considerable importance because NO regulates a number of neurotransmitter functions.

Animals↗

PubMedDate not supplied

Manganese-induced developmental neurotoxicity in the CD rat: is oxidative damage a mechanism of action?

Inhalation of high concentrations of manganese (Mn) is associated with an extrapyramidal motor disorder in humans. Oxidative damage, mediated by increased levels of Mn in dopaminergic brain regions and mitochondria, is a hypothesized mechanism of action for Mn-induced neuronal degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an increased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of MnCl2 from postnatal day (PND) 1 to 49 Brain regional and mitochondrial Mn levels, brain regional reactive oxygen species (ROS) levels, and whole-brain nuclear and mitochondrial 8-OHdG levels were used to evaluate Mn-mediated oxidative damage. High-dose Mn exposure was associated with increased spontaneous motor activity on PND 21 and decreased body weights on PND 49. On PND 21, Mn concentrations were increased in brain regions and mitochondrial fractions in both low- and high-dose groups. ROS levels were elevated in cerebellum but not striatum. On PND 49, Mn concentrations in brain regions and mitochondrial fractions were increased only in the high-dose group. Mn exposure did not significantly alter 8-OHdG levels in either mitochondrial or nuclear DNA. Selective uptake of Mn by the striatum or mitochondrial fraction was not demonstrated at either time point. These data allow us to conclude that oral exposure to high levels of Mn in developing CD rats resulted in increased brain regional and mitochondrial Mn levels, increased motor activity, and decreased body weights but not in selective accumulation of Mn in the striatum or mitochondrial fraction of any brain region or elevations in striatal ROS or whole-brain 8-OHdG levels. These findings do not support the hypothesis that oxidative damage, as assessed by ROS and 8-OHdG levels, is a mechanism of action in Mn-induced developmental neurotoxicity in the CD rat.

Administration, Oral↗

PubMedDate not supplied

Modulation of avian muscarinic cholinergic high affinity binding sites by a neurotoxic organophosphate.

A systematic survey of a series of high affinity binding sites in the forebrain of hens treated with a neurotoxic organophosphate has been carried out. Fourteen month old laying hens were treated with 750 mg/kg body weight triorthocresyl phosphate (TOCP) orally in gelatin capsules. Control birds received empty capsules. After 21 d, hens were killed and forebrain membrane fractions prepared for binding studies using the nitrocellulose filtration method. Incubations were carried out in the presence of low concentrations of pharmacological agents selective for certain classes of receptor sites. Nonspecific binding was characterized by simultaneous incubations in the presence of excess competing unlabeled ligands. Binding criteria that were satisfied in a prior study included specificity, saturability, and attainment of equilibrium during incubation. No significant change was found in treated hens assayed for dopaminergic, GABA, glycinergic, beta-adrenergic, and benzodiazepine receptors. However, a 30% reduction in binding of 3H-quinuclidinyl benzilate was apparent in TOCP-treated hens. These data implied a selective reduction of muscarinic receptors, suggesting a down-regulation in response to cholinergic hyperactivity. This dose of TOCP also caused paralysis and ataxia in all treated hens 21 d after exposure to the toxicant. These data demonstrate that a selective lesion in cholinergic neurotransmitter circuitry can be caused by a single administration of TOCP.

Acetylcholinesterase↗