Cerebral Palsy

Secondary brain damage following traumatic brain injury in part depends on neuroinflammation, a process where genetic factors may play an important role. We examined the response to a standardized cortical contusion in two different inbred rat strains, Dark Agouti (DA) and Piebald Virol Glaxo (PVG). Both are well characterized in models of autoimmune neuroinflammation, where DA is susceptible and PVG resistant. We found that infiltration of polymorphonuclear granulocytes (PMN) at 3-day postinjury was more pronounced in PVG. DA was more infiltrated by T cells at 3-day postinjury, showed an enhanced glial activation at 7-day postinjury and higher expression of C3 complement at 7-day postinjury. Neurodegeneration, assessed by Fluoro-Jade, was also more pronounced in the DA strain at 30-day postinjury. These results demonstrate differences in the response to cortical contusion injury attributable to genetic influences and suggest a link between injury-induced inflammation and neurodegeneration. Genetic factors that regulate inflammation elicited by brain trauma may be important for the development of secondary brain damage.

Temporal lobe epilepsy is the most common form of epilepsy in humans. Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. The objectives of this work were to comparatively study the inhibitory action of antioxidants (ascorbic acid or alpha-tocopherol) on behavioral changes and brain damage induced by high doses of pilocarpine, aiming to further clarify the mechanism of action of these antioxidant compounds. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (250 or 500 mg/kg, i.p.) and alpha-tocopherol (200 or 400 mg/kg, i.p.) on the behavior and brain lesions observed after seizures induced by pilocarpine (400 mg/kg, i.p., P400 model) in rats. Ascorbic acid or alpha-tocopherol injections prior to pilocarpine suppressed behavioral seizure episodes. These findings suggested that free radicals can be produced during brain damage induced by seizures. In the P400 model, ascorbic acid and alpha-tocopherol significantly decreased cerebral damage percentage. Antioxidant compounds can exert neuroprotective effects associated with inhibition of free radical production. These results highlighted the promising therapeutic potential of ascorbic acid and alpha-tocopherol in treatments for neurodegenerative diseases.

Oxidative DNA damage can be the consequence of endogenous metabolic processes and exogenous insults and several DNA repair enzymes provide protection against the toxic effects of oxidized DNA bases. Here we review the increasing knowledge on the relationship between an oxidized dNTPs pool and genome instability. The review also describes some important progress toward understanding the role of oxidative DNA damage and its repair in neurodegenerative diseases. In particular the hMTH1 hydrolase destroys oxidized nucleic acid precursors to prevent their harmful incorporation into DNA and RNA. Based on results obtained in our transgenic mouse overexpressing hMTH1 in the brain we discussed the mechanisms by which this hydrolase protects against neurodegeneration in Huntington disease models. Copyright © 2010. Published by Elsevier B.V.

Angiotensin-converting enzyme (ACE) inhibitors are widely used as blood pressure medications in hypertensive individuals. However, ACE inhibitors also play an integral role in the breakdown of neuronal substance P, which has been recently implicated in the development of functional deficits following traumatic brain injury (TBI). The present study therefore examined the effects of ACE inhibitors on histological and motor outcome following TBI. Male Sprague-Dawley rats were treated with Captopril, Enalapril or equal volume saline for 7 days prior to the induction of diffuse TBI using the impact acceleration model. At 5h post-injury, animals administered Captopril demonstrated significantly increased substance P immunoreactivity compared to vehicle controls (p<0.01), and increased dark cell change that persisted to 7 days post-trauma. Captopril also resulted in exacerbated motor deficits compared to vehicle treated animals (p<0.05) as assessed by the rotarod test over a 7-day post-traumatic period. Administration of the alternative ACE inhibitor, Enalapril, likewise exacerbated motor deficits, confirming a class effect of ACE inhibitors rather than a compound effect specific to Captopril. We conclude that ACE inhibitors are deleterious to outcome following TBI, presumably by impairing the degradation of substance P and increasing substance P mediated neuronal injury. Copyright © 2010. Published by Elsevier Ireland Ltd.

In patients with major depression or in animal models of depression, significantly increases in the concentrations of pro-inflammatory cytokines have been consistently reported. Proinflammatory cytokines can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to release stress hormone, glucocorticoids. As a consequence of excessive inflammatory response triggered by pro-inflammatory cytokines in the periphery, free radicals, oxidants and glucocorticoids are over-produced, which can affect glial cell functions and damage neurons in the brain. Indeed, decreased neurogenesis and the dysfunction of neurotrophic system (up- or down-regulations of neurotrophins and their receptors) have been recently found. Effective treatments for depressive symptoms, such as antidepressants and omega-3 fatty acids can increase or modulate neurotrophic system and enhance neurogenesis. However, the relationship between glial cells; microglia (mostly involved in neuroinflammation) and astrocytes (producing neurotrophins), and the contribution of inflammation to decreased neurogenesis and dysfunction of neurotrophic system are almost unknown. This review first introduces changes in behavior, neurotransmitter, cytokine and neurogenesis aspects in depressed patients and several animal models of depression, secondly explores the possible relationship between pro- and anti-inflammatory cytokines and neurogenesis in these models, then discusses the effects of current treatments on inflammation, neurotrophic system and neurogenesis, and finally pointes out the limitations and future research directions. Copyright © 2010. Published by Elsevier Inc.

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Copyright © 2010. Published by Elsevier B.V.

Activated JNK has been reported to be located in nucleus in mild cases of Alzheimer’s disease (AD), but is exclusively in cytoplasm in more advanced stages of AD and implicated in its pathogenesis, suggesting that activation and re-distribution of JNK correlates with the progress of AD. The present study was designed to investigate the role of JNK in intracerebroventricular streptozotocin (i.c.v. STZ) induced cognitive impairment and oxidative stress. Streptozotocin has been observed to impair learning and memory, increase oxidative-nitritive stress, induce cholinergic hypofunction and neuronal damage in rat brain. Chronic treatment with SP600125 from day 10 to 28 following i.c.v. STZ injections significantly improved spatial memory, attenuate oxidative-nitritive stress. In addition, significant increase in acetylcholinesterase activity and lactate dehydrogenase (LDH) levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Whereas, SP600125 treatment significantly restored acetylcholinesterase activity and reduced LDH levels indicating restorative capacity of SP600125 with respect to cholinergic functions and preventing the neuronal damage. In line with previous report, the current study also supports the potential of JNK inhibition as a possible therapeutic strategy to ameliorate neurodegenerative disorders associated with oxidative stress and cognitive impairment. Copyright © 2010. Published by Elsevier Inc.

There is consensus that the left hemisphere plays a dominant role in language processing, but functional imaging studies have shown that the right as well as the left posterior inferior frontal gyri (pIFG) are activated when healthy right-handed individuals make phonological word decisions. Here we used online transcranial magnetic stimulation (TMS) to examine the functional relevance of the right pIFG for auditory and visual phonological decisions. Healthy right-handed individuals made phonological or semantic word judgements on the same set of auditorily and visually presented words while they received stereotactically guided TMS over the left, right or bilateral pIFG (n= 14) or the anterior left, right or bilateral IFG (n= 14). TMS started 100ms after word onset and consisted of four stimuli given at a rate of 10Hz and intensity of 90% of active motor threshold. Compared to TMS of aIFG, TMS of pIFG impaired reaction times and accuracy of phonological but not semantic decisions for visually and auditorily presented words. TMS over left, right or bilateral pIFG disrupted phonological processing to a similar degree. In a follow-up experiment, the intensity threshold for delaying phonological judgements was identical for unilateral TMS of left and right pIFG. These findings indicate that an intact function of right pIFG is necessary for accurate and efficient phonological decisions in the healthy brain with no evidence that the left and right pIFG can compensate for one another during online TMS. Our findings motivate detailed studies of phonological processing in patients with acute and chronic damage of the right pIFG. Copyright © 2010. Published by Elsevier Ltd.

The aim of our study was to investigate neuroprotective properties of shikonin, a naphthoquinone pigment isolated from the roots of the traditional Chinese herb Lithospermum erythrorhizon. In the present study, mice were divided randomly into sham, model, shikonin and edaravone-treated groups. Shikonin (50, 25, 12.5 mg/kg, i.g.) or maize oil was administered three times before ischemia and once at 2 h after the onset of ischemia. Mice were anesthetized with chloral hydrate and subjected to middle cerebral artery 2 h of occlusion and then 22 h of reperfusion. Different antioxidant assays were employed in order to evaluate the antioxidant activities of shikonin in vitro. Neurological deficit, infarct size, histopathology changes and oxidative stress markers were evaluated after 22 h of reperfusion. In comparison with model group, treatment with shikonin significantly decreased neurological deficit scores, infarct size, the levels of malondialdehyde(MDA), carbonyl and reactive oxygen species, and attenuated neuronal damage, up-regulated superoxide dismutase(SOD), catalase, glutathione peroxidase(GSH-Px) activities and reduced glutathione(GSH)/ glutathione disulfide (GSSG) ratio. Taken together, these results suggested that neuroprotective effects of shikonin against cerebral ischemia/reperfusion injury maybe attributed to its antioxidant effects. Copyright © 2010 Elsevier B.V. All rights reserved.

Metachromatic leukodystrophy (MLD) is a lysosomal disorder caused by arylsulfatase A (ARSA) deficiency. It is classified into three forms according to the age of onset of symptoms (late infantile, juvenile, and adult). We carried out a cross-sectional and retrospective study, which aimed to determine the epidemiological, clinical, and biochemical profile of MLD patients from a national reference center for Inborn Errors of Metabolism in Brazil. Twenty-nine patients (male, 17) agreed to participate in the study (late infantile form: 22; juvenile form: 4; adult form: 1; asymptomatic: 2). Mean ages at onset of symptoms and at biochemical diagnosis were, respectively, 19 and 39 months for late infantile form and 84.7 and 161.2 months for juvenile form. The most frequently reported first clinical symptom/sign of the disease was gait disturbance and other motor abnormalities (72.7%) for late infantile form and behavioral and cognitive alterations (50%) for juvenile form. Leukocyte ARSA activity level did not present significant correlation with the age of onset of symptoms (r = -0.09, p = 0.67). Occipital white matter and basal nuclei abnormalities were not found in patients with the late infantile MLD. Our results suggest that there is a considerable delay between the age of onset of signs and symptoms and the diagnosis of MLD in Brazil. Correlation between ARSA activity and MLD clinical form was not found. Further studies on the epidemiology and natural history of this disease with larger samples are needed, especially now when specific treatments should be available in the near future.