dizocilpine-maleate and cysteine-sulfinic-acid

Expression of the N-methyl-D-aspartate receptor (NMDAr) and its involvement in cellular proliferation is well-known in tumors of neuronal tissue, such as glioma and neuroblastoma. We have investigated NMDAr expression in the normal, hyperplastic and neoplastic human prostate by immunohistochemistry. Low stromal NMDAr immunostaining was observed in 2 of 12 (17%) normal prostate specimens, but epithelial NMDAr staining was not seen. Of 18 benign prostatic hyperplasia (BPH) specimens, none had stromal NMDAr staining, but 2 had low and 1 had high epithelial NMDAr immunoreactivity. Moderate to high NMDAr immunostaining was observed in the stroma of 60 of 145 (41%) prostate cancer (PCa) specimens. Epithelial NMDAr staining was low in 26 (18%) and moderate to high in 36 (25%) of 145 PCa specimens. We have also examined the effects of the NMDAr antagonist memantine on the growth of ten human cancer cell lines: four prostate, two breast and four colon. The NMDAr antagonist memantine inhibited in-vitro growth of all ten cell lines, with half-maximal growth-inhibition at 5 to 20 microg/ml (23 to 92 microM) memantine. An NMDA agonist, L-cysteinesulfinic acid, stimulated cellular proliferation of all ten cell lines, with maximal growth-stimulation (30% to 75%, depending on the cell line) observed between doses of 33 to 66 microM. Our data provide evidence for the expression and activity of NMDAr in prostate cancer.

Topics: Breast; Cell Line; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Cysteine; Dizocilpine Maleate; Humans; Immunohistochemistry; Male; Memantine; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, N-Methyl-D-Aspartate

Excitotoxic amino acids contain two acidic groups, but cysteine represents an exception to this rule. The hypothesis that cysteine toxicity is mediated by the oxidized and diacidic metabolites cysteine sulphinate and/or cysteate was tested in the present study. The issue was approached in three different ways. Firstly, the distribution of brain injury after subcutaneous administration of cysteine (1 mg/g) to 4-day-old rats was compared with that caused by cysteine sulphinate (3 mg/g). Secondly, the effects of excitatory amino acid receptor antagonists on cysteine and cysteine sulphinate toxicity were investigated. Thirdly, the cerebral concentrations of cysteine sulphinate were determined after cysteine administration and compared with those obtained after cysteine sulphinate injection. The cerebral cortex was the region most vulnerable to cysteine toxicity, followed by the hippocampus (especially the medial subicular neurons), amygdala, caudoputamen, cerebellum and septum. Pronounced extravasation of red blood cells was observed in lesioned areas. One day after cysteine administration, the injury was infarction-like and sharply demarcated. Cysteine sulphinate-induced damage resembled cysteine-induced lesions in some respects: the anterior cingulate and retrosplenial cortices, as well as medial subicular cells, were quite vulnerable. However, the differences prevailed. Cysteine sulphinate, but not cysteine, killed neurons of the superficial part of the tectum, the medial habenula, the ventromedial hypothalamus and the arcuate nucleus. Further, while cysteine toxicity was prominent in deep cortical layers, cysteine sulphinate preferentially damaged superficial cortical neurons. Cysteine toxicity was abolished by pretreatment with MK-801, a selective NMDA antagonist, but not by 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline, a selective AMPA receptor blocker. In contrast, the considerably smaller lesion seen after cysteine sulphinate administration was only partially prevented by MK-801. Large (19-fold) increases in cortical cysteine sulphinate concentration were noted after injection of a toxic dose of cysteine. This corresponds to 90 nmol cysteine sulphinate/g protein. The cysteate concentration was not increased above the detection limit. Injection of a toxic dose of cysteine sulphinate elevated cysteine sulphinate concentration in the frontomedial cortex (a region consistently injured by cysteine sulphinate) almost three orders of magnitude more

Topics: Amino Acids; Animals; Animals, Newborn; Brain; Cerebral Cortex; Cysteic Acid; Cysteine; Dizocilpine Maleate; Female; Male; Nerve Degeneration; Neurons; Neurotoxins; Neurotransmitter Agents; Organ Specificity; Quinoxalines; Rats; Rats, Sprague-Dawley