Effects of the novel cyclosporine derivative PSC833 on glucose metabolism in rat primary cultures of neuronal and glial cells.
Cyclosporine A (CsA) and the cyclosporine degrees congener PSC833 are known to cause transient CNS symptoms at high dosages in animal and man. Since impaired glucose metabolism plays a fundamental role in many heriditary and drug-induced neurological disorders, it was the purpose of the present study to evaluate whether this mechanism of pathogenesis might apply to PSC833 and CsA, using neural cells from rats. PSC833 and CsA were investigated in primary cultures of rat neuronal and glial cells at the concentration of 0.1, 1, 10, and 20 microM for 24 and 48 hr. Lactate dehydrogenase was determined as a marker of cytotoxicity. Cell proliferation was determined in astrocytes. Cellular glucose metabolism was investigated by 13C-NMR using [1-13C]glucose as a substrate. Glucose and lactate concentrations in the cell culture supernatants were determined spectrophotometrically. PSC833 at 10 microM was not cytotoxic in neuronal or glial cells nor did it inhibit proliferation in astrocytes 24 hr after incubation. Under the same conditions, the determination of [1-13C]glucose and [3-13C]lactate revealed significantly increased glucose consumption and lactate production in both cell types, as well as decreased levels of Krebs cycle intermediates. In the cell culture medium of both cell types after treatment with 10 microM PSC833, the rates of glucose consumption and lactate formation increased in comparison to controls, between 60-83% and 54-78%, respectively. PSC833 (10 microM) and CsA (20 microM) resulted in nearly similar increased glucose consumption and lactate production. The major PSC833 metabolite in rats, M9, which was devoid of CNS effects, did not cause significant changes in glucose metabolism. The present data suggest that PSC833-impaired tricarboxylic acid cycle activity, resulting in decreased Krebs cycle metabolites, can cause energy depletion and acidosis, which might contribute to the transient neurological symptoms of PSC833 and CsA.
Cruz
F
F
Novartis Pharma AG, Experimental Toxicology, CH-4002, Basel, Switzerland.
Wolf
A
A
D000818:Animals; D002247:Carbon Isotopes; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D009682:Magnetic Resonance Spectroscopy; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002247:Carbon Isotopes; D003524:Cyclosporins; D019344:Lactic Acid; D005947:Glucose; C070272:valspodar