CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1G93A mice with a C57BL/6 background.

The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1G93A mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1G93A mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

OBJECTIVES: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury. METHODS: Adult rats underwent transient middle cerebral artery occlusion after atorvastatin pretreatment (5 or 10 mg/ kg/day; po; 30 days) with or without CoQ10 (200 mg/kg/day). After 24 hours ischemic/reperfusion injury, animals were subjected to functional assessments followed by cerebral molecular and histological to detect inflammation, apoptosis and oxidative stress. RESULTS: Animals dosed with 10 mg/kg presented the worst neurological function and brain damage in the acute phase of stroke injury. CoQ10 supplementation efficiently improved functional deficit and cerebral infarction in all stroke animals, particularly those exhibiting statin toxicity. Such benefits were associated with remarkable anti-inflammatory and anti-apoptotic effects, based on the analyzed tumor necrosis factor-α, interleukin-6, Bax/Bcl2 and cleaved caspase 3/9 immunoblots. Importantly, our fluoro-jade staining data indicated CoQ10 may revert the stroke-induced neurodegeneration. No parallel alteration was detected in stroke-induced oxidative stress as determined by malondialdehyde and 8-oxo-2'-deoxyguanosine levels. DISCUSSION: These data suggest that all stroke animals may benefit from CoQ10 administration through modulating inflammatory and degenerative pathways. This study provides empirical evidence for potential advantages of CoQ10 supplementation in atorvastatin-receiving patients which may not shadow its antioxidant properties.

Postpartum depression and role of serum trace elements.

Postpartum depression (PPD) is a major depressive disorder that most often emerges within 6 to 12 weeks of delivery, but can happen any time up to 1 year after birth. In developed countries, the incidence of postnatal depression is about 10-15% in adult women depending upon the diagnostic criteria, timing of screening and screening instruments used. Mothers with depressive symptoms have been found to have more complex behavioral contacts with their children; this situation can damage family relationships, and even leads to infanticide. Various pathophysiologies are proposed for postpartum depression: Nutritional deficiencies, iron deficiency anemia, rapid decrease in the levels of reproductive hormones following delivery, alterations in hypothalamic-pituitary-adernocortical mechanism and alterations in neurotransmitter levels. Among pathophysiologies of postpartum depression, the role of trace elements is highlighted. The purpose of this review is to assess the role of trace elements including zinc, magnesium, iron and copper in PPD. Zinc as a trace element has the second highest concentration of all transition metals in the brain, and its deficiency is associated with behavioral disturbances. Lower zinc blood concentration was found in women with postpartum depression. Another trace element, magnesium, also influences the nervous system via its actions on the release and metabolism of neurotransmitters. Various studies have focused on antidepressant-like effects of magnesium and its deficiency has been reported in depression. Depletion of magnesium stores during pregnancy is hypothesized to be the cause of postpartum depression. Iron deficiency is the most common single nutrient deficiency in the world. There is an association between anemia and depressive disorders. Copper has been recognized as an essential element for many years. Iron also plays a vital role in neurological disorders and its levels are relevant to postpartum depression. Involvement of trace elements can be seen in pathophysiologies of PPD in different ways. Therefore, trace element supplementation can be an alternative treatment for patients with PPD.