Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine.

The finding of increased activity of the enzyme extracellular superoxide dismutase in four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type (PME-UL) prompted the addition of antioxidants to these patients' treatment regimen. After 6 months treatment with vitamin E, selenium, riboflavin, and zinc, there was some improvement in patient awareness and speech. N-acetylcysteine (NAC) is a sulfhydryl antioxidant that increases cellular glutathione and the activity levels of several antioxidant enzymes and has additional actions that contribute to its demonstrated efficacy in preventing or decreasing damage in models of neuronal toxicity. We treated the affected siblings with 4 to 6 grams a day of NAC in addition to the other antioxidants and magnesium. There has been a marked decrease in myoclonus and some normalization of somatosensory evoked potentials with NAC treatment. The patients were treated with NAC for up to 30 months with continued beneficial effects. NAC may prevent further deterioration in the clinical course of patients with PME-UL and may be indicated in other neurodegenerative conditions where excess free radical activity may contribute to disease progression.

Application of trace metal analysis to basic problems in neurobiology studies of patients with Reye's syndrome.

Reye's syndrome (Rs) is an acute illness in children manifested by encephalopathy and fatty degeneration of the liver. The syndrome may be secondary to injury of mitochondria following a toxic insult in a susceptible individual with a viral illness. Since the response to infection often involves a change in trace metals, we investigated the metal status of patients with Rs. Decreased levels of serum and liver selenium (Se) and copper (Cu) were demonstrated via PIXE analysis, in addition to an increase in serum iron (Fe) and zinc (Zn). In a subsequent study using a rat animal model of Rs, the hepatotoxin 4-pentenoic acid (4-PA) produced similar changes in serum and liver trace metals. Serum and liver Se levels were also significantly depleted in rats exposed to another toxin, valproic acid (VPA). Aspirin, known to complex metals, may also be associated with Rs. Rats chronically exposed to aspirin had decreased serum Se, Fe, and Zn compared to controls. Selenium was also decreased in liver, as was Cu. Atomic absorption spectrophotometric analysis of serum and liver Cu for mice exposed to aspirin and influenza A virus were also studied. In liver, Cu was significantly decreased in mice on Cu-deficient diets but, not in control mice exposed to virus, or aspirin and virus. For the Se-deficient animals, liver Cu was not different from controls, but there was an increase in tissue Cu for Se-sufficient mice exposed to virus and aspirin; Cu levels were decreased in sera of this latter group. Serum Cu was increased in Cu-sufficient mice exposed to virus and aspirin. The above data are of biologic and toxicologic interest because of metalloenzyme localization in the mitochondrial matrix, the cellular compartment showing the greatest degree of pathologic change in Rs. In particular, Se-dependent gluthathione peroxidase is a major deterent of peroxidative damage of lipid membranes. The accumulated evidence suggests that alteration of trace metals, e.g., decrease in Se, may promote peroxidation of mitochondrial membranes in patients with Rs.

ACTH acts via an anterior ventral third ventricular site to elicit grooming behavior.

Intracerebroventricular but not parenteral application of ACTH has been shown to elicit excessive grooming behavior in rats and mice. This behavior is elicited by administration of ACTH into the lateral, third, or fourth ventricles. Plugging of the cerebral aqueduct with cold cream fails to prevent grooming in response to lateral ventricle injection of ACTH. However, cold cream plugs in the third ventricle can prevent the subsequent induction of grooming behavior by lateral ventricle injection of ACTH, but only when the plugs are located in the anterior ventral third ventricle in the region of the organum vasculosum laminae terminalis (OVLT) and median eminence. These data suggest the anterior ventral third ventricle as the periventricular site of action of ACTH in eliciting excessive grooming, although it is possible that peptides taken up in this area are transported to other regions to elicit the behavioral response.

Selenium, zinc, and copper changes with valproic acid: possible relation to drug side effects.

Side effects of treatment with the anticonvulsant valproic acid (VPA) suggested the possibility of alteration of trace metal status. Administration of VPA for 1 week produced significant depletion of zinc and selenium in plasma of rats and a one-third reduction of hepatic selenium. Patients who were treated chronically, with VPA as the sole anticonvulsant medication, had decreased plasma selenium levels. Most cases of VPA-associated hepatotoxicity occur in children. This could be due to decreased selenium concentrations when mechanisms for protection against peroxidative damage are not fully developed.

Cerebral 2-deoxyglucose accumulation in mice following chronic treatment with an ACTH4-9 analog, ORG 2766.

Mice were treated with [MET(O2)4, D-Lys8,Phe9]ACTH4-9 (ORG 2766, 100 micrograms/kg per day SC) for 10 days. On the tenth day mice were injected with [3H]2-deoxyglucose and its cerebral accumulation determined in 17 brain areas. The combined results of four experiments indicated a significant decrease of the 2-deoxyglucose accumulation in the septum. Changes observed in other brain areas were not statistically significant in the combined analysis of all four experiments. This selective change in the septum is consistent with selective uptake of ORG 2766 in this region, and with the lack of behavioral activity of ACTH in septal lesioned animals. It also suggests that the behavioral activity of this peptide, generally considered to be on arousal, vigilance, and/or selective attention, may be mediated through the septum, a limbic system structure.

Regional glucose metabolism in mouse brain following ACTH peptides and naloxone.

Following intracerebroventricular (ICV) injection of ACTH1-24 significant decreases in 2-deoxyglucose (2DG) uptake were observed in frontal cortex and pyriform cortex, and an increase in thalamus. No such changes were observed following ICV MSH/ACTH4-10. Regional changes in 2DG uptake in olfactory bulb, pyriform cortex, thalamus and cerebellum were significantly correlated with the excessive grooming induced by ACTH1-24. Grooming behavior not induced by ACTH1-24 was not correlated with 2DG changes in any of these regions. Naloxone treatment did not significantly alter the regional pattern of 2DG uptake. In naloxone-pretreated mice ACTH1-24 did not induce significant changes in regional 2DG uptake. Following a series of footshocks, 2DG uptake increased in the hypothalamus, tectum and hippocampus. This pattern of changes is different from that observed following ICV ACTH1-24 and cannot therefore be attributed to ACTH secretion during the stress.

Neurotensin induces catalepsy in mice.

Intracerebroventricular (i.c.v.) injection of neurotensin (NT) induced catalepsy in mice at doses greater than or equal to 0.02 microgram. The cataleptic effect progressively increased, reaching a maximum at approx. 2 hr after injection. In contrast, the hypothermic effect of neurotensin reached a maximum 1 hr after the injection, and was declining at 2 hr. Not all mice that showed hypothermia also showed catalepsy, and some mice showed catalepsy without hypothermia. Catalepsy induced by intracerebroventricular injection of neurotensin was not significantly correlated with the hypothermia. Furthermore, oxotremorine induced hypothermia without catalepsy. Thus, several lines of evidence indicate that the catalepsy induced by neurotensin is not the consequence of the neurotensin induced hypothermia. Thyrotropin releasing hormone (TRH), injected either intracerebroventricularly with neurotensin, or intraperitoneally before neurotensin abolished the hypothermia but only diminished the catalepsy scores. The cataleptic effect of neurotensin is consistent with its other neuroleptic-like activities.

Homocysteine induced convulsions: enhancement by vitamin B6 and inhibition by hydrazine.

The effects of pyridoxal phosphate, pyridoxine and hydrazine were studied on homocysteine-induced seizures in mice. Both of the B6 vitamers significantly decreased the latency and increased the severity, lethality and duration of seizures induced by homocysteine. The B6 inhibitor hydrazine sulfate, which is normally a convulsant, prevented the tonic component of the convulsions and increased the latency to the clonic component. This experiment indicates that a vitamin B6 dependent step is critically involved in the metabolic changes which precede homocysteine seizures.

Focal and generalized experimental seizures induced by homocysteine.

Electrocorticographic and behavioral effects of parenteral injections of homocysteine in rats are described. Homocysteine activates experimental foci and produces focal seizures in experimental animals with pre-existing lesions. It produces generalized ECoG seizures and generalized convulsions in unlesioned animals in higher doses.

Chronic focal epileptiform discharges induced by injection of iron into rat and cat cortex.

A single injection of 5 or 10 microliters of ferrous or ferric chloride into rat or cat sensorimotor cortex resulted in chronic recurrent focal paroxysmal electroencephalographic discharges as well as behavioral convulsions and electrical seizures. Recurrent focal epileptiform discharge caused by cortical injection of iron salts suggests that the development of human posttraumatic epilepsy may depend, in part, on the neurochemical alterations induced by the principal metallic ions found in whole blood.