Concepción Nava-Ruiz

Brain regional lipid peroxidation and metallothionein levels of developing rats exposed to cadmium and dexamethasone.

Cadmium (Cd) is neurotoxic metal which induces histopathological damage and oxidative stress through free radicals over production. Metallothionein (MT) is a protein able to scavenge free radicals and to chelate metals. In this study we describe the lipid peroxidation (LPO) and MT content in the brain of developing rats exposed at Cd 1 mg/kg/day intra peritoneally (i.p.) and dexamethasone (Dx) 2 mg/kg/day (i.p.) alone and combined during 5 days. At those doses, cadmium significantly increases the levels of LPO in parietal cortex, striatum and cerebellum as compared to a control group while, in the hippocampus no modifications in the LPO levels were observed. In the group treated with Cd+Dx, Dx significantly diminished the levels of LPO in parietal cortex, striatum and cerebellum. On the other hand, the MT levels showed a significant increase in all regions of the groups treated with Dx and Cd+Dx as compared with the control group. These results show that Dx treatment prevented the increase in LPO levels associated to Cd exposure, probably through the increase in MT content.

Lead neurotoxicity: effects on brain nitric oxide synthase

Lead (Pb), a ubiquitous and potent neurotoxicant, induces several neurophysiological and behavioural changes, while Pb alters the function of multiple organs and systems, it primarily affects the central nervous system. In human adults, encephalopathy resulting from Pb intoxication is often characterized by sleeplessness, poor attention span, vomiting, convulsions and coma; in children, Pb-induced encephalopathy is associated with mental dullness, vomiting, irritability and anorexia; diminished cognitive function resulting in a mental deficit has been also observed during Prolonged exposure to Pb. Pb can produce oxidative stress, disrupt the blood–brain barrier and alter several Ca2+-dependent processes, including physiological processes that involve nitric oxide synthesis on central nervous system in development and adult animals. This review summarizes recent evidence showing that Pb can interfere with the production of nitric oxide and can disrupt the function of nitric oxide synthase. Lead interferes with nitric oxide-related physiological mechanisms, and Pb neurotoxicity may affect processes involved in learning and memory.

Oxidative Stress Associated with Neuronal Apoptosis in Experimental Models of Epilepsy

Epilepsy is considered one of the most common neurological disorders worldwide. Oxidative stress produced by free radicals may play a role in the initiation and progression of epilepsy; the changes in the mitochondrial and the oxidative stress state can lead mechanism associated with neuronal death pathway. Bioenergetics state failure and impaired mitochondrial function include excessive free radical production with impaired synthesis of antioxidants. This review summarizes evidence that suggest what is the role of oxidative stress on induction of apoptosis in experimental models of epilepsy.

Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats

Although dapsone (4,4′‐diaminodiphenylsulfone) has been described as a neuroprotective agent in occlusive focal ischemia in rats, its mechanism of action is still unknown. To explore this mechanism, oxidative, inflammatory and apoptotic processes were evaluated in the striatum of adult rats using a model of ischemia‐reperfusion (I/R), either with or without dapsone treatment. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2 hr, followed by reperfusion. Rats were dosed either with dapsone (12.5 mg/kg i.p.) or vehicle 30 min before or 30 min after the ischemia onset. Lipid peroxidation (LP) and nitrotyrosine contents were measured 22 hr after reperfusion, and myeloperoxidase activity was evaluated 46 hr after I/R. Different markers for apoptosis and necrosis were also evaluated both at 24 and 72 hr after I/R experimental procedure. LP increased by 37% in ischemic animals vs controls, and this effect was reversed by dapsone treatments. A similar effect was observed regarding nitrotyrosine striatal contents. Myeloperoxidase activity, a marker of inflammatory response, increased 3.7‐fold in ischemic animals vs. control rats, and dapsone treatment antagonized that effect. Although apoptosis was increased by the effect of ischemia at both evaluation times, dapsone antagonized that effect only at 72 hr after surgery. Dapsone antagonized all of the I/R end points measured, showing a remarkable ability to decrease markers of damage through antioxidant, antiinflammatory, and anti‐apoptotic effects.

Brain lesions induced by chronic cocaine administration to rats.

Cocaine is a common drug of abuse, and its use has emerged as a major public health problem with neurological complications. In this work, the authors studied microscopic lesions produced in brain by chronic cocaine administration to rats. Twenty-five Wistar rats were exposed to 30 mg/kg/day ip of cocaine and sacrificed at 15, 30, 45, 60, and 90 days after treatment and compared to 25 control rats injected daily with saline. The parietal cortex (Cx), hippocampus (Hp), substantia nigra (SN), and cerebellum (Ce) were morphologically analyzed. The authors found progressive light microscopic lesions in all regions studied, including nuclear pyknosis and atrophy, interstitial edema, broken fibers, and necrosis. Results show that chronic treatment with cocaine in rats leads to selective severe lesions in different brain regions.

Nitric oxide synthase immunolocalization and expression in the rat hippocampus after sub-acute lead acetate exposure in rats

Interference with nitric oxide production is a possible mechanism for lead neurotoxicity. In this work, we studied the effects of sub-acute lead administration on the distribution of NOS isoforms in the hippocampus with respect to blood and hippocampal lead levels. Lead acetate (125, 250 and 500ppm) was given via drinking water to adult male Wistar rats for 14 days. We determined blood and hippocampal lead levels by atomic absorption spectrophotometry. Antibodies against three isoforms of NOS were used to analyze expression and immunolocalization using western blotting and immunohistochemistry, respectively. Blood and hippocampal lead levels were increased in a dose-dependent manner in groups treated with lead acetate. We found diminished expression and immunoreactivity of nNOS and eNOS at 500ppm as compared to the control group. No expression and immunoreactivity was observed in hippocampus for iNOS. The observed high levels of lead in the blood reflect free physiological access to this metal to the organism and were related to diminished expression and immunoreactivity for nNOS and eNOS.

Immunohistochemical Study of Nrf2-Antioxidant Response Element as Indicator of Oxidative Stress Induced by Cadmium in Developing Rats

In developing animals, Cadmium (Cd) induces toxicity to many organs including brain. Reactive oxygen species (ROS) are often implicated in Cd-inducedtoxicity and it has been clearly demonstrated that oxidative stress interferes with the expression of genes as well as transcriptional factors such as Nrf2-dependent Antioxidant Response Element (Nrf2-ARE). Cd-generated oxidative stress and elevated Nrf2 activity have been reported in vitro and in situ cells. In this study we evaluated the morphological changes and the expression pattern of Nrf2 and correlated them with the Cd concentrations in different ages of developing rats in heart, lung, kidney, liver, and brain. The Cd content in different organs of rats treated with the metal was increased in all ages assayed. Comparatively, lower Cd brain levels were found in rats intoxicated at the age of 12 days, then pups treated at 5, 10, or 15 days old, at the same metal dose. No evident changes, as a consequence of cadmium exposure, were evident in the morphological analysis in any of the ages assayed. However, Nrf2-ARE immunoreactivity was observed in 15-day-old rats exposed to Cd. Our results support that fully developed blood-brain barrier is an important protector against Cd entrance to brain and that Nrf2 increased expression is a part of protective mechanism against cadmium-induced toxicity.

Cadmium, Lead, Thallium: Occurrence, Neurotoxicity and Histopathological Changes of the Nervous System

Metals, particularly heavy metals such as lead, cadmium and thallium between others, constitute significant potential threats to human health in both occupational and environmental settings. Metals toxicity most commonly involves the kidney, liver and mainly nervous system. Neurons in general have a high metabolic rate, which makes them more susceptible to different heavy metals producing changes in neuronal function may lead to secondary alterations in neuronal anatomy. Neuropathology is frequently used to evaluate the effects of toxic agents on nervous system organization and cellular components; thus, careful histologic evaluations increase our knowledge of the neurotoxicity of heavy metals. Structural changes can often be correlated with altered neurochemistry, behavior, and electrophysiologic function.

Histochemical changes in muscle of rats exposed subchronically to low doses of heavy metals

Heavy metals are ubiquitous in the environment and exposure through food and water as well as occupational sources can constitute a potential threat to human health. The mechanisms of heavy metal damage include the production of free radicals that alter mitochondrial activity, affecting cellular types like neurons and muscular fibres. We examined whether rats exposed subchronically via drinking water to low doses of heavy metals can produce alterations in muscle. Results showed that the proportion of ragged red fibres increased in muscle of rats exposed to lead and thallium, likewise slight changes in enzymatic activity of muscular fibres were also observed.

Metallothionein in Brain Disorders

Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I–IV), three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.