Cysteine-induced hypoglycemic brain damage: an alternative mechanism to excitotoxicity.
Central neural damage caused by L-cysteine (L-Cys) was first reported more than 30 years ago. Nevertheless, the exact mechanisms of L-Cys-mediated neurotoxicity are still unclear. Preliminary study in mice demonstrated that, following L-Cys injection, animals developed tachypnea, tremor, convulsions, and death in conjunction with documented hypoglycemia. The aim of the present study was to further investigate the mechanism of L-Cys-mediated hypoglycemic effect and neural damage. Neonatal ICR mice (n=6) were injected with L-Cys (0.5-1.5 mg/g body weight [BW]), and their blood glucose and insulin levels were determined up to 90 min following the injection. Experiments were repeated in chemically (streptozotocin [STZ]) pancreatectomized animals. Brain histology was assessed. Mice injected with L-Cys exhibited dose-dependent neurotoxicity and higher mortality as compared with controls. L-Cys (1.2-1.5 mg/g BW) caused severe hypoglycemia (glucose<42 mg/dl) ( P<0.001). In STZ-treated (diabetic) animals, L-Cys (1.5 mg/g BW) increased plasma insulin levels 2.3-fold and decreased serum glucose levels by 50% ( P<0.01). Brain histology revealed destruction of as much as 51% of hippocampal neurons in the L-Cys-treated mice but not in the glucose-resuscitated animals. These findings suggest that L-Cys injection can cause pronounced hypoglycemia and central neural damage which is glucose reversible. Since L-Cys is chemically different from the other excitatory amino acids (glutamate and aspartate), L-Cys-mediated neurotoxicity may be connected to its hypoglycemic effect.
Gazit
V
V
Laboratory for Anesthesia, Pain and Neural Research, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Ben-Abraham
R
R
Coleman
R
R
Weizman
A
A
Katz
Y
Y
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000008:administration & dosage / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007003:Hypoglycemia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D013311:Streptozocin / Q000494:pharmacology; D015996:Survival Rate; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D003545:Cysteine