Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease.

A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed.

Effect of Argemone mexicana (L.) against lithium-pilocarpine induced status epilepticus and oxidative stress in Wistar rats.

Argemone mexicana (L.) has a role in the treatment of epileptic disorders in Indian traditional system of medicine. We studied its effect on induced status epilepticus (SE) and oxidative stress in rats. SE was induced in male albino rats by administration of pilocarpine (30 mg/kg, ip) 24 h after injection of lithium chloride (3 mEq/kg, ip). Different doses of the ethanol extract of A. mexicana were administered orally 1 h before the injection of pilocarpine. The severity of SE was observed and recorded every 15 min for 90 min and thereafter at every 30 min for another 90 min, using the Racine scoring system. In vivo lipid peroxidation of rat brain tissue was measured utilizing thiobarbiturate-reactive substances. Both in vitro free radical nitric oxide and 2,2-diphenyl-1-picryl hydrazyl scavenging activities of the extract were also determined. The SE severity was significantly reduced following oral administration of the extract at 250, 500 and 1000 mg/kg doses. None of the animals from groups 3 to 5 (with A. mexicana extract) have exhibited forelimb clonus of stage 4 seizure. The extract also exhibited both in vivo and in vitro antioxidant activities.

The heart-placenta axis in the first month of pregnancy: induction and prevention of cardiovascular birth defects.

Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects (CHDs). Considering that approximately 49% of pregnancies are unplanned, this period of pregnancy can be considered high-risk for cardiac, as well as for neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. Using avian and mouse vertebrate models, we demonstrated that FA supplementation prevents CHD induced by alcohol, lithium, or elevation of the metabolite homocysteine, a marker for FA deficiency. All three factors affected the important Wnt signaling pathway by suppressing Wnt-mediated gene expression in the heart fields, resulting in a delay of cardiomyocyte migration, cardiomyogenesis, and CHD. Optimal protection of cardiogenesis was observed to occur with FA supplementation provided upon morning after conception and at higher doses than the presently available in prenatal vitamin supplementation. Our studies demonstrate pathways and cell processes that are involved with protection of one-carbon metabolism during heart development.

Toxicity of lithium to humans and the environment--a literature review.

Lithium concentrations in the surface and underground waters may be higher than general environment in places where lithium-rich brines and minerals occur, and in places where lithium batteries are disposed of. This review has indicated that lithium is not expected to bioaccumulate and its human and environmental toxicity are low. Lithium is not a dietary mineral for plants but it does stimulate plant growth. Large doses of lithium (up to 10 mg/L in serum) are given to patients with bipolar disorder. At 10 mg/L of blood, a person is mildly lithium poisoned. At 15 mg/L they experience confusion and speech impairment, and at 20 mg/L Li there is a risk of death. A provisional recommended daily intake of 14.3 microg/kg body weight lithium for an adult has been suggested.

[Lithium intoxications at normal serum levels]. / Schwere lithiumintoxikationen bei normalen serumspiegeln.

OBJECTIVE: Lithium is known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication or full blown intoxications even when lithium levels are normal. Our aim was to detect predicting factors of lithium neurotoxicity at normal serum lithium levels in order to allow prevention of those constellations. METHODS: We report two cases of severe lithium intoxications at normal serum lithium levels and review the current literature concerning lithium neurotoxicity at normal serum levels. RESULTS: It appears that the probability of developing signs of lithium intoxications in patients treated with lithium is increased with advanced age, co-morbidity with pre-existing neurological or other general diseases, especially those associated with fever, and in combination with the use of antipsychotics, antidepressants or mood stabilizers. The serum lithium level does not necessarily detect an intoxication. CONCLUSIONS: In patients developing signs of intoxication under lithium therapy, further investigations should include serum levels and an EEG. Because intoxications can occur even in normal serum levels, discontinuation of lithium medication should be taken into account on the basis of clinical signs of intoxication.

[Preclinical toxicological study of the new enterosorbent noolit].

The safety of the new enterosorbent noolit has been evaluated within the framework of its preclinical characterization. Single introduction of noolit to rats and mice (females and males) in maximum doses for intragastric administration (5.0 - 20.0 g/kg) does not lead to the loss of experimental animals. Single administration of large doses (5 - 40 times the effective dose) can reduce the growth of the total body weight and lead to the development of nonlethal pathological changes of hemopoietic organs, which is manifested by a weak regenerative anemia (5% of cases); neutrophile, eosinophile, and basophile leukocytosis (3% of cases); and a decrease in the glucose level in blood serum. In chronic experiments on rabbits, the administration of noolit for 3 months in a dose of 0.5 and 2.0 g/kg (2 and 8 times that recommended for humans) did not reveal any toxic action on the functional and morphological state of the main systems and organs (blood, liver, kidneys, lungs, heart, gastrointestinal tract, sex organs, etc.).