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Biomedical subjects

S L Rao

Publications and source records attributed to S L Rao.

At least 19 recordsLinked to original sources
PubMed1999

Neurotoxic potential of three structural analogs of beta-N-oxalyl-alpha,beta-diaminopropanoic acid (beta-ODAP).

Lathyrism is a non-progressive motor neuron disease produced by consumption of the excitatory amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (beta-ODAP). To learn more about the mechanisms underlying Lathyrism three structural analogs of beta-ODAP were synthesized. Carboxymethyl-alpha,beta-diaminopropanoic acid (CMDAP) evoked inward currents which were antagonized by APV (30 microM), but not by CNQX (10 microM). N-acetyl-alpha,beta-diaminopropanoic acid (ADAP) evoked no detectable ionic currents but potentiated N-methyl-D-aspartate (NMDA)-activated currents. The potentiation of NMDA currents by ADAP was blocked by 7-chlorokynurenic acid. Carboxymethylcysteine (CMC) did not activate any detectable ionic currents. None of the three beta-ODAP analogs produced visible symptoms of toxicity in day old chicks when administered for 2-3 consecutive days. Ligand binding studies demonstrated that all the three compounds were effective to in displacing [3H]glutamate. The maximum inhibition was 92% for CMDAP, 61% for ADAP, 65% for CMC and 99% for beta-ODAP. These data indicate that analogs of beta-ODAP may interact with glutamate receptors without producing neurotoxicity.

Amino Acids, Diamino↗
PubMed1999

Remediation of attention deficits in head injury.

Head injury is associated with psychological sequelae which impair the patient's psychosocial functioning. Information processing, attention and memory deficits are seen in head injuries of all severity. We attempted to improve deficits of focused, sustained and divided attention. The principle of overlapping sources of attention resource pools was utilised in devising the remediation programme. Tasks used simple inexpensive materials. Four head injured young adult males with post concussion syndrome underwent the retraining program for one month. The patients had deficits of focused, sustained and divided attention parallel processing, serial processing, visual scanning, verbal learning and memory and working memory. After the retraining programme the deficits of attention improved in the four patients. Serial processing improved in two patients. Parallel processing and neuropsychological deficits did not improve in any patient. The symptom intensity reduced markedly and behavioural functioning improved in three of the four patients. The results supported an association between improving attention and reduction of symptom intensity. Attention remediation shows promise as a cost effective, time efficient and simple technique to improve the psychological and psychosocial functioning of the head injured patient.

Adult↗
PubMed1998

In vivo metabolism of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid: the Lathyrus sativus neurotoxin in experimental animals.

A comparative study of the metabolism of 1,2,3 (14)C-ODAP and 4,5 (14)C-ODAP in mice, rats and chicks has been carried out. Following oral administration of 1,2,3 (14)C-ODAP to either black or white mice, nearly 16% of the radioactivity appeared in the expired CO2 within 8 h, while in the rat only 3% of it appeared and in chicks it was less than 2%. No 14CO2 appeared in the expired air in mice given 4,5 (14)C-ODAP. Electrophoregrams of the spot urine samples from the animals given 1,2,3 (14)C-ODAP showed the presence of one radioactive metabolite (metabolite-1) in addition to ODAP. While the urine from rats and mice given 4,5 (14)C-ODAP indicated the presence of metabolite-1 as well as 14C-oxalate, in chicks, however, no 14C-oxalate was present and only metabolite-1 could be detected. The results indicate that ODAP can to some extent undergo oxidation in vivo in mice (and to a lesser extent in rats) leading to the formation of CO2 and oxalate and a similar pathway might be more prominent in humans leading to a near complete oxidation of ODAP.

Amino Acids, Diamino↗
PubMed1998

Receptor interactions of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid, the Lathyrus sativus putative excitotoxin, with synaptic membranes.

Direct evidence for the excitotoxicity of 3-N-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP), the Lathyrus sativus neurotoxin has been studied by examining the binding of chemically synthesized [2,3 3H]ODAP ([3H]ODAP) to synaptic membranes. [3H]ODAP binding to membranes was mostly nonspecific, with only a very low specific binding (15-20% of the total binding) and was also not saturable. The low specific binding of [3H]ODAP remained unaltered under a variety of assay conditions. A low Bmax of 3.2 +/- 0.4 pmol/mg and Kd 0.2 +/- 0.08 microM could be discerned for the high affinity interactions under conditions wherein more than 80-90% of the binding was nonspecific. While ODAP could inhibit the binding of [3H]glutamate to chick synaptic membranes with a Ki of 10 +/- 0.9 microM, even L-DAP, a non neurotoxic amino acid was also equally effective in inhibiting the binding of [3H]glutamate. The very low specific binding of [3H]ODAP to synaptic membranes thus does not warrant considering its interactions at glutamate receptors as a significant event. The results thus suggest that the reported in vitro excitotoxic potential of ODAP may not reflect its true mechanism of neurotoxicity.

Amino Acids, Diamino↗
PubMed1997

Inhibition of tyrosine aminotransferase by beta-N-oxalyl-L-alpha,beta-diaminopropionic acid, the Lathyrus sativus neurotoxin.

Species differences in susceptibility are a unique feature associated with the neurotoxicity of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (L-ODAP), the Lathyrus sativus neurotoxin, and the excitotoxic mechanism proposed for its mechanism of toxicity does not account for this feature. The present study examines whether neurotoxicity of L-ODAP is the result of an interference in the metabolism of any amino acid and if it could form the basis to explain the species differences in susceptibility. Thus, Wistar rats and BALB/c (white) mice, which are normally resistant to L-ODAP, became susceptible to it following pretreatment with tyrosine (or phenylalanine), exhibiting typical neurotoxic symptoms. C57BL/6J (black) mice were, however, normally susceptible to L-ODAP without any pretreatment with tyrosine. Among the various enzymes associated with tyrosine metabolism examined, the activity of only tyrosine aminotransferase (TAT) was inhibited specifically by L-ODAP. The inhibition was noncompetitive with respect to tyrosine (Ki = 2.0 +/- 0.1 mM) and uncompetitive with respect to alpha-ketoglutarate (Ki = 8.4 +/- 1.5 mM). The inhibition of TAT was also reflected in a marked decrease in the rate of oxidation of tyrosine by liver slices, an increase in tyrosine levels of liver, and also a twofold increase in the dopa and dopamine contents of brain in L-ODAP-injected black mice. The dopa and dopamine contents in the brain of only L-ODAP-injected white mice did not show any change, whereas levels of these compounds were much higher in tyrosine-pretreated animals. Also, the radioactivity associated with tyrosine, dopa, and dopamine arising from [14C]tyrosine was twofold higher in both liver and brain of L-ODAP-treated black mice. Thus, a transient increase in tyrosine levels following the inhibition of hepatic TAT by L-ODAP and its increased availability for the enhanced synthesis of dopa and dopamine and other likely metabolites (toxic?) resulting therefrom could be the mechanism of neurotoxicity and may even underlie the species differences in susceptibility to this neurotoxin.

Amino Acids, Diamino↗
PubMed1983

beta-N-gamma-glutamyl diaminopropionic acid, a convulsant and an inhibitor of brain glutamate decarboxylase.

The different isomers of the dipeptide beta-N-gamma-glutamyl diaminopropionate inhibit L-glutamate-1-carboxylyase (GAD, EC-4.1.1.15) activity in mouse brain homogenates. The L-D isomer is the most effective as an inhibitor, while the D-D isomer is least inhibitory. The different isomers are neurotoxic to mice and the chick, the L-D isomer being the most toxic. The neurotoxicity of the isomers in mice was also associated with a significant lowering in GAD activity in the brains of convulsing mice.

Animals↗
PubMed1983

Cell Wall Composition of Neurospora crassa Under Conditions of Copper Toxicity.

The mycelia of Neurospora crassa grown in the presence of high concentrations of copper were blue in color, but only on a medium containing inorganic nitrate and phosphate as the nitrogen and phosphate sources, respectively. The cell wall isolate of the blue mycelia contained large amounts (12%) of copper and higher amounts of chitosan, phosphate, and amino groups, with a 42% decrease in the chitin content. Although all the glucosamine of the cell wall of control cultures could be released within 6 h of hydrolysis with acid, that of the blue mycelium required prolonged hydrolysis for 24 h. On removal of copper, the cell wall of the blue mycelium could quantitatively bind again to copper as well as to zinc. Although zinc binding was fivefold greater, copper alone was preferentially bound from a mixture of the two metal ions. Supplementation of iron along with copper in the culture medium resulted in the disappearance of the blue color of the mycelium and restoration of normal growth and composition of the cell wall, probably by limiting the uptake of copper from the medium. The possibility of the cell wall being a specific site of lesion in copper toxicity in the mold is discussed.

Journal Article↗
PubMed1975

Chemical synthesis of N beta-oxalyl-L-alpha, beta-diaminopropionic acid and optical specificity in its neurotoxic action.

A practical procedure is described for the bulk synthesis of the neurotoxin N beta-oxalyl-L-alpha, beta-diaminopropionic acid (OA2pr3), a potential dicarboxylic amino acid antagonist of Lathyrus sativus seeds. L-Aspartic acid was reacted with sodium azide in 30% fuming sulfuric acid and L-alpha, beta-diaminopropionic acid hydrochloride (A2pr3-HCl) was isolated in yields greater than 75%. Potassium methyl oxalate was found to react selectively with the beta-amino group of S2pr3 resulting in near quantitative yields of OA2pr3. D-OA2pr3 has been made for the first time by this procedure. Unlike L-OA2pr3 the naturally occurring neurotoxin, D-OA2pr3, is not neuroactive even in high doses. The microsynthesis of L-[2,3-3H]A2pr3 from L-[2,3-3H]aspartic acid is also described, and the same procedure could also be used to prepare the neurotoxin with other labels. The availability of the neurotoxin in bulk and in labeled form should further experimental approaches to the understanding of its mechanism of action.

Amino Acids, Diamino↗