Francisco J. Medina

Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3‐nitropropionic model of Huntington's disease

An investigation was conducted on the effect of transcranial magnetic field stimulation (TMS) on the free radical production and neuronal cell loss produced by 3‐nitropropionic acid in rats. The effects of 3‐nitropropionic acid were evaluated by examining the following changes in: the quantity of hydroperoxides and total radical‐trapping antioxidant potential (TRAP), lipid peroxidation products, protein carbonyl groups, reduced glutathione (GSH) content, glutathione peroxidase (GSH‐Px), catalase and succinate dehydrogenase (SDH) activities; total nitrite and cell death [morphological changes, quantification of neuronal loss and lactate dehydrogenase (LDH) levels]. Our results reveal that 3‐nitropropionic acid induces oxidative and nitrosative stress in the striatum, prompts cell loss and also shows that TMS prevents the harmful effects induced by the acid. In conclusion, the results show the ability of TMS to modify neuronal response to 3‐nitropropionic acid.

Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington's disease rat model: effects on neurotrophic factors and neuronal density

There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntingtons disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool.

17 β-Estradiol may affect vulnerability of striatum in a 3-nitropropionic acid-induced experimental model of Huntington's disease in ovariectomized rats

The aim of present study was to clarify the role of female sex hormones in the development and course of neurodegenerative disease in an experimental model of Huntingtons disease induced by 3-nitropropionic acid (NPA) (30 mg/kg intraperitoneally (i.p.)/day for 4 days) in ovariectomized rat. Gonadectomy prompted oxidative stress and cell death evaluated by the detection of caspase-3, whereas 3-nitropropionic acid enhanced the oxidative stress induced by ovariectomy and it triggered cell damage characterized by increases of LDH levels. These changes were prevented by administration of 17 beta-estradiol. Our findings suggested that: (i) ovariectomy induced oxidative stress and apoptosis in the brain; (ii) 3-nitropropionic acid exacerbated oxidative stress induced by ovariectomy and shifting cell to cell death; and (iii) 17 beta-estradiol administration decreased oxidative stress and cell death induced by ovariectomy and 3-nitropropionic acid. These results revealed that sex ovarian hormones play a important role in onset and development of neurodegenerative diseases, as well as neuroprotective effects of 17 beta-estradiol against the changes induced ovariectomy and ovariectomy plus 3-nitropropionic acid.

Effect of transcranial magnetic stimulation on oxidative stress induced by 3-nitropropionic acid in cortical synaptosomes.

This study evaluates the effect of transcranial magnetic stimulation (TMS; 60 Hz and 0.7 mT) treatment on 3-nitropropionic acid (20 mg/kg i.p./day for 4 days)-induced oxidative stress in cortical synaptosomes of Wistar rats. The oxidative derangement was confirmed by a high level of lipid peroxidation products and protein carbonyls, together with a decreased in reduced glutathione (GSH) content, catalase and GSH-peroxidase (GSH-Px) activities. Additionally, it was observed a reduction in succinate dehydrogenase (SDH) activity. All changes were partially prevented or reversed by administration of TMS. These results show that TMS reduces oxidative stress in cortical synaptosomes, and suggest that TMS may protect neuronal and maintain synaptic integrity.

Huntington's disease: the value of transcranial meganetic stimulation.

Huntingtons disease (HD) is a genetic neurodegenerative process whose etiology is based on a localized disturbance in the short arm of chromosome 4 that encodes the huntingtin protein (Htt). The elongation of triple CAG for glutamine characterizes this change. Mutated Htt (mHtt) causes the appearance of intracellular aggregates inducing alterations in mitochondrial metabolism in the form of reactive oxygen species (ROS) and ATP depletion. The oxidative imbalance caused by mHtt leads the neurons to a state of oxidative stress resulting in damage to macromolecules and cellular death. Since the discovery of certain mechanisms underlying the pathogenesis of HD, several therapeutic procedures have been shown to delay or slow the evolution of the condition and have demonstrated the biochemical and molecular mechanism involved. The studies have reported that transcranial magnetic stimulation (TMS) may improve motor and other symptoms associated with neurodegenerative and neuropsychiatric processes such as major depression, schizophrenia, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, progressive muscle atrophy, multiple sclerosis, stroke, Alzheimers disease, Parkinsons disease or HD. This study focuses on the effect of TMS on oxidative stress and neurogenesis in studies and its possible usefulness in HD.

Extremely low-frequency electromagnetic fields activate the antioxidant pathway Nrf2 in a Huntington's disease-like rat model.

Transcranial magnetic stimulation (TMS) is a non-invasive technique used recently to treat different neuropsychiatric and neurodegenerative disorders. Despite its proven value, the mechanisms through which TMS exerts its beneficial action on neuronal function remain unclear. Recent studies have shown that its beneficial effects may be at least partly due to a neuroprotective effect on oxidative and cell damage. This study shows that TMS can modulate the Nrf2 transcriptor factor in a Huntingtons disease-like rat model induced by 3-nitropropionic acid (3-NP). Western blot analysis demonstrated that 3-NP caused a reduction in Nrf2 in both cytoplasm and nucleus, while TMS applied to 3-NP-treated rats triggered an increase in cytoplasm and nucleus Nrf2 levels. It was therefore concluded that TMS modulates Nrf2 expression and translocation and that these mechanisms may partly explain the neuroprotective effect of TMS, as well as its antioxidant and cell protection capacity.

Protective effect of nicotine on oxidative and cell damage in rats with depression induced by olfactory bulbectomy.

We evaluated the effects of nicotine on cell and oxidative damage caused by olfactory bulbectomy (OBX). The rats were divided into seven groups as follows: i) control; ii) vehicle (6% ethanol); iii) treated with nicotine; iv) sham operated; v) olfactory bulbectomy (OBX); vi) OBX+vehicle; and vii) OBX+Nic. The OBX was performed using the trepanation of frontal bone. The olfactory bulbs were cut and removed without damage to the frontal cortex. Two weeks after surgery nicotine was administered chronically once daily for 14 days, intraperitoneally (i.p.) in doses of 1.5 mg/kg, two weeks after surgery. OBX caused an increase in lipid peroxidation products and caspase-3 but prompted a reduction in reduced glutathione (GSH) content and antioxidative enzyme activity. All these changes were reverted by treatment of nicotine (14 days). In conclusions: i) OBX induces oxidative stress and cell death by apoptosis; and ii) nicotine presents antidepressant and antioxidant effect. All these findings suggest that nicotine would be a therapeutic tool for depression, although more studies are needed in this area to define the appropriate treatment regime.

Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma

In neurodegenerative diseases, progressive oxidative stress is a major event that precedes neuronal death. Oxidative stress is characterized by an imbalance between oxidants and antioxidants. This imbalance induced oxidative molecular and cell damage, reducing cellular viability. 3-Nitropropionic acid (3NP) causes oxidative stress and other molecular and cellular changes similar to those observed in neurons of patients with Huntington’s disease. Since carvedilol and melatonin act as free-radical scavengers, this study examined the effect of carvedilol (10−5 M) and melatonin (10−5 M) on oxidative and cell damage induced by 3NP in N1E-115 neuroblastoma cells. Carvedilol and melatonin prevented the increases in lipid peroxidation and total LDH activity, as well as the depletion of reduced glutathione (GSH) and the reduction of antioxidative enzymes activities in N1E-115 cells incubated with 100 mM 3NP. All these carvedilol and melatonin effects were more intense when the drugs were added before rather than after inducing the damage by 3NP. These results also provided evidence supporting the hypothesis that carvedilol and melatonin can be useful for treating neurodegenerative diseases, such as Huntington’s disease.

Mechanisms and pathways underlying the therapeutic effect of transcranial magnetic stimulation.

Abstract It has been almost 40 years since Barker, Jalinous, and Freeston designed and used the first device of transcranial magnetic stimulation (TMS). From then until now, this technique has evolved vertiginously, appearing a lot of new protocols and device modifications, which associated with new technologies complement and enhance the versatility of this technique. TMS has demonstrated to be a safe technology and become a key tool in the study of the complex brain processes. Despite this, it is as a therapeutic tool where this technique has caused a revolution. In this regard, this type of non-invasive brain stimulation has been proven useful in a variety of neurodegenerative and psychiatric disorders due to its biochemical, molecular, and cellular effects, with depression being the paradigm of the therapeutic effectiveness of this technique. This review focuses on a detailed vision of how this type of radiation modifies different biochemical and cellular processes that induce the mechanisms and pathways underlying the therapeutic effects of TMS.

Skeletal muscle findings in experimental autoimmune encephalomyelitis.

INTRODUCTION Skeletal muscle is a target organ in multiple sclerosis, a chronic debilitating disease of the central nervous system caused by demyelination and axonal deterioration. Since the experimental autoimmune encephalomyelitis model reproduces the relapsing-remitting course found in most multiple sclerosis patients, this model was used to compare the histological features of skeletal muscle at onset with those observed at the start of the second relapse. MATERIAL AND METHODS Histological, histochemical and ultrastructural changes, as well as biochemical oxidative damage and antioxidant-system markers, were examined in the soleus and extensor digitorum longus muscles of Dark Agouti rats in which experimental autoimmune encephalomyelitis had been induced by active immunization using myelin oligodendrocyte glycoprotein. RESULTS Histological examination at disease onset revealed ragged-red fibers and ultrastructural evidence of mitochondrial degeneration. At the second relapse, neurogenic changes included a wide range of cytoarchitectural lesions, skeletal muscle atrophy and the appearance of intermediate fibers; however, differences were observed between soleus and extensor digitorum longus lesions. Biochemical tests disclosed an increase in oxidative stress markers at onset, which was more pronounced at the second relapse. CONCLUSIONS Microscopic findings suggest that two patterns can be distinguished at disease onset: an initial phase characterized by muscle mitochondrial alterations, and a second phase dominated by a histological muscle pattern of clearly neurogenic origin.