Melatonin Improves Behavioral and Biochemical Outcomes in a Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease followed only by Alzheimer's disease and affects millions of people worldwide. Despite the plethora of preclinical and clinical studies, there is currently a paucity of therapeutic agents for PD that can promote neuroprotection. In addition, the therapeutic agents currently available only help with improvement of PD symptoms. Therefore, it is imperative to find new therapeutic avenues for PD patients to minimize the economic and social burden on the concerned families. Rotenone is a frequently used neurotoxin in developing a PD model to aid in understanding the mechanisms of neuronal death. In addition, several studies have investigated the effects of melatonin, a neurohormone that is neuroprotective in various neurological diseases due to its anti-apoptotic, anti-inflammatory, and anti-oxidative properties. Our study investigated the role of melatonin-induced tyrosine hydroxylase (TH) and sensory motor function in a rotenone rat model to determine whether melatonin had any positive effects. Our results revealed that melatonin improves motor function by upregulation of TH in striatum of the brain. In addition, melatonin inhibits the striatal degeneration as shown by histopathological analysis. Therefore, results from the current study provide evidence for melatonin as a promising candidate for effective future therapeutic strategies for PD.

Telmisartan Ameliorates Astroglial and Dopaminergic Functions in a Mouse Model of Chronic Parkinsonism.

Many studies reported the neuroprotective effects of angiotensin II type 1 receptor (AT1R) antagonists in Parkinson's disease (PD). However, the role of AT1R blockade on astroglial, in turn, dopaminergic functions in chronic PD is still to be studied. In the present study, telmisartan (TEL; 3 and 10 mg/kg/day; p.o), was used to study the effects AT1R blockade on astrocytic and dopaminergic functions in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsonism (250 mg/kg, i.p, in 10 equally divided doses at 3.5 days interval) in C57BL/6 J mice. TEL significantly downregulated glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), TNFα and IL1ß expressions and nitric oxide (NO) content. Significant upregulation glial cell derived neurotrophic factor (GDNF) expression and increased glutathione (GSH) content reveal the ameliorating effects of TEL on astroglial functions. On the other hand, TEL upregulated tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) expressions. Finally, TEL improved dopamine and its turnover and restored locomotor performance. Present experiment reveals that TEL has the potential to alleviate astroglial functions, apart from restoring dopaminergic functions, at least in part. To conclude, TEL may be a better disease-modifying therapeutic regimen in the management of Parkinsonism, acting primarily via astroglial-dopaminergic functions.

Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion.

The recent suggestion that growth differentiation factor 11 (GDF11) acts as a rejuvenation factor has remained controversial. However, in addition to its role in aging, the relationship between GDF11 and cerebral ischemia is still an important area that needs more investigation. Here we examined effects of GDF11 on angiogenesis and recovery of neurological function in a rat model of stroke. Exogenous recombinant GDF11 (rGDF11) at different doses were directly injected into the tail vein in rats subjected to cerebral ischemia/reperfusion (I/R). Neurobehavioral tests were performed, the proliferation of endothelial cells (ECs) and GDF11 downstream signal activin-like kinase 5 (ALK5) were assessed, and functional microvessels were measured. Results showed that rGDF11 at a dosage of 0.1 mg/kg/day could effectively activate cerebral angiogenesis in vivo. In addition, rGDF11 improved the modified neurological severity scores and the adhesive removal somatosensory test, promoted proliferation of ECs, induced ALK5 and increased vascular surface area and the number of vascular branch points in the peri-infarct cerebral cortex after cerebral I/R. These effects were suppressed by blocking ALK5. Our novel findings shed new light on the role of GDF11. Our results strongly suggest that GDF11 improves neurofunctional recovery from cerebral I/R injury and that this effect is mediated partly through its proangiogenic effect in the peri-infarct cerebral cortex, which is associated with ALK5. Thus, GDF11/ALK5 may represent new therapeutic targets for aiding recovery from stroke.

Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease.

Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY13-36 in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage of Y2R using selective non-peptide small molecule Y2R antagonist SF31 in vivo and in vitro. Our results showed that activation of Y2R with intranasal NPY or NPY13-36 led to an improved motor function in R6/2 mice as revealed by rotarod performance, vertical pole test, and hindlimb clasping behaviour. Also, intranasal NPY or NPY13-36 led to a decrease in aggregated mHtt and mediated increase in dopamine and cAMP-regulated phosphoprotein, 32kDa (DARPP-32), brain-derived neurotrophic factor (BDNF), and activated extracellular signal-regulated protein kinases (pERK1/2) levels in R6/2 mice. Intranasal NPY or NPY13-36 had no effect on body weight but showed positive effects on survival in R6/2 mice. Furthermore, intranasal NPY or NPY13-36 attenuated induction of proinflammatory cytokine and inflammatory mediators in R6/2 mice. In contrast, antagonizing by using SF31 exacerbates phenotypic severity in R6/2 mice and treatment effects with either intranasal NPY or NPY13-36 were significantly blocked.In vitro, using inducible PC12/HttQ103-EGFP cells, treatment with NPY or NPY13-36 protected against mHtt-mediated neuromorphological defects (neurite length and soma area) and neurotoxicity but had no effect on mHtt inclusion body formation. Conversely, co-treatment with SF31 significantly inhibited these effects. Together, our findings extend previous evidence of the beneficial effects of NPY in R6/2 mice, and more importantly, suggest that targeted activation of Y2R receptor might be a promising disease-modifying target for HD and other neurodegenerative diseases.

Influence of growth hormone replacement on neurological and psychomotor development. Case report / Influência da reposição do hormônio do crescimento no desenvolvimento neuropsicomotor. Relato de caso

ABSTRACT The height response to the use of growth hormone in short height cases has already been confirmed in the literature. The influence of the insulin-like growth factor 1 (GH-IGF1) axis components on development, function, regeneration, neuroprotection, cognition, and motor functions has been evaluated in experimental studies and in adults with central nervous system lesions. However, there is still little research on the clinical impact of hormone replacement on neurological and psychomotor development. This report presents the case of a patient with excellent weight-height recovery and, even more surprisingly, neurological and psychomotor development in response to use of growth hormone. The result strengthens the correlation between experimental and clinical findings related to cerebral plasticity response to growth hormone in children. A preterm male patient with multiple health problems during the neonatal and young infancy period, who for six years presented with a relevant deficit in growth, bone maturation, and neurological and psychomotor development. At six years of age, he had low stature (z-score −6.89), low growth rate, and low weight (z-score −7.91). He was incapable of sustaining his axial weight, had not developed fine motor skills or sphincter control, and presented with dysfunctional swallowing and language. Supplementary tests showed low IGF-11 levels, with no changes on the image of the hypothalamus-pituitary region, and bone age consistent with three-year-old children — for a chronological age of six years and one month. Growth hormone replacement therapy had a strong impact on the weight-height recovery as well as on the neurological and psychomotor development of this child.

RESUMO A resposta estatural ao uso de hormônio do crescimento na baixa estatura já está comprovada na literatura. A influência dos componentes do eixo fator de crescimento semelhante à insulina tipo 1 (GH-IGF1) sobre desenvolvimento, função, regeneração, neuroproteção, cognição e funções motoras tem sido avaliada em estudos experimentais e em adultos com lesão de sistema nervoso central. No entanto, ainda são poucas as pesquisas sobre o impacto clínico da reposição hormonal no desenvolvimento neuropsicomotor. Este relato apresenta o caso de um paciente com excelente recuperação pôndero-estatural e, de forma ainda mais surpreendente, de desenvolvimento neuropsicomotor, em resposta ao uso de hormônio do crescimento. O resultado observado fortalece a correlação entre achados experimentais e clínicos, no que diz respeito à resposta da plasticidade cerebral ao hormônio do crescimento em crianças. Paciente do sexo masculino nasceu pré-termo com múltiplos agravos no período neonatal e de lactente jovem, e que, por 6 anos, apresentou deficit relevante do crescimento, na maturação óssea e do desenvolvimento neuropsicomotor. Aos 6 anos de idade, apresentava baixa estatura (escore Z de −6,89), baixa velocidade de crescimento e baixo peso (escore Z de −7,91). Era incapaz de sustentar o peso axial, não tinha desenvolvido habilidade motora fina e nem controle esfincteriano, e apresentava também disfunção na deglutição e na linguagem. Exames complementares mostraram IGF1 baixo, sem alterações na imagem da região hipotálamo-hipofisária e idade óssea compatível com 3 anos — para a idade cronológica de 6 anos e 1 mês. A terapia de reposição com hormônio do crescimento promoveu forte impacto na recuperação pôndero-estatural e também do desenvolvimento neuropsicomotor desta criança.

Neuroprotective effect of resveratrol on rotenone-treated C57BL/6 mice.

The aim of the present study was to investigate whether resveratrol could reduce nigral iron levels to prevent the degeneration of dopaminergic neurons in the substantia nigra (SN) of C57BL/6 mice induced by rotenone. Parkinson's disease (PD) is an age-related neurodegenerative disorder; elevated iron levels in the SN participate in neuronal death in PD. Resveratrol is a kind of polyphenolic compounds and possess antioxidant, anticancer, and anti-inflammatory biological functions. Although many research groups have investigated the neuroprotective effects of resveratrol against PD, the precise mechanisms underlying its beneficial effects on dopaminergic neuron are poorly defined. In this study, rotenone-treated mice were used to examine neuroprotective roles of resveratrol in PD. Sixty-four adult C57BL/6 mice were divided into four groups: vehicle control mice, rotenone mice, resveratrol-treated rotenone mice, resveratrol mice. In the present study, we found that chronic administration of rotenone significantly induced motor coordination impairment and increased iron levels and dopaminergic neuron loss in SN in mice. Resveratrol administration significantly protected mice from rotenone-induced motor coordination impairment, elevated iron levels, and dopaminergic neuronal loss. Our results show that resveratrol can elicit neuroprotective effects on rotenone-induced parkinsonism through reducing nigral iron levels.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. RESULTS: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. CONCLUSION: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

Lithium increases hippocampal SNARE protein abundance after traumatic brain injury.

Rodent models of traumatic brain injury (TBI) reproduce secondary injury sequela and cognitive impairments observed in patients afflicted by a TBI. Impaired neurotransmission has been reported in the weeks following experimental TBI, and may be a contributor to behavioral dysfunction. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, the machinery facilitating vesicular docking and fusion, is a highly-conserved mechanism important for neurotransmission. Following TBI, there is a reduction in both the formation of the SNARE complex and the abundance of multiple SNARE proteins, including the chaperone protein cysteine string protein α (CSPα). Treatment with lithium in naïve rats reportedly increases the expression of CSPα. In the context of TBI, brain-injured rats treated with lithium exhibit improved outcome in published reports, but the mechanisms underlying the improvement are poorly understood. The current study evaluated the effect of lithium administration on the abundance of SNARE proteins and SNARE complex formation, hemispheric tissue loss, and neurobehavioral performance following controlled cortical impact (CCI). Sprague Dawley rats were subjected to CCI or sham injury, and treated daily with lithium chloride or vehicle for up to 14days. Administration of lithium after TBI modestly improved spatial memory at 14days post-injury. Semi-quantitative immunoblot analysis of hippocampal lysates revealed that treatment with lithium attenuated reductions in key SNARE proteins and SNARE complex formation at multiple time points post-injury. These findings highlight that treatment with lithium increased the abundance of synaptic proteins that facilitate neurotransmission and may contribute to improved cognitive function after TBI.

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.

The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [3H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). RESULTS: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α. CONCLUSIONS: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.

Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1(G93A) mice model of ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, involving both upper and lower motor neurons. The disease is induced by multifactorial pathologies, and as such, it requires a multifaceted therapeutic approach. CXCR4, a chemokine receptor widely expressed in neurons and glial cells and its ligand, CXCL12, also known as stromal-cell-derived factor (SDF1), modulate both neuronal function and apoptosis by glutamate release signaling as well as hematopoietic stem and progenitor cells (HSPCs) migration into the blood and their homing towards injured sites. Inhibition approaches towards the CXCR4/CXCL12 signaling may result in preventing neuronal apoptosis and alter the HSPCs migration and homing. Such inhibition can be achieved by means of treatment with AMD3100, an antagonist of the chemokine receptor CXCR4. METHODS: We chronically treated male and female transgenic mice model of ALS, SOD1(G93A) mice, with AMD3100. Mice body weight and motor function, evaluated by Rotarod test, were recorded once a week. The most effective treatment regimen was repeated for biochemical and histological analyses in female mice. RESULTS: We found that chronic administration of AMD3100 to SOD1(G93A) mice led to significant extension in mice lifespan and improved motor function and weight loss. In addition, the treatment significantly improved microglial pathology and decreased proinflammatory cytokines in spinal cords of treated female mice. Furthermore, AMD3100 treatment decreased blood-spinal cord barrier (BSCB) permeability by increasing tight junction proteins levels and increased the motor neurons count in the lamina X area of the spinal cord, where adult stem cells are formed. CONCLUSIONS: These data, relevant to the corresponding disease mechanism in human ALS, suggest that blocking CXCR4 by the small molecule, AMD3100, may provide a novel candidate for ALS therapy with an increased safety.

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.

BACKGROUND: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. METHODS: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. RESULTS: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. CONCLUSIONS: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.

Antidepressant fluvoxamine reduces cerebral infarct volume and ameliorates sensorimotor dysfunction in experimental stroke.

The sigma-1 receptor has been reported to be associated with diverse biological activities including cellular differentiation, neuroplasticity, neuroprotection, and cognitive functioning of the brain. Fluvoxamine, one of the currently known antidepressants, is a sigma-1 receptor agonist; its effectiveness in treating acute cerebral ischemia has not been reported. We studied the in-vivo effects of this compound using an animal model of focal cerebral ischemia. Forty male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and assigned to five treatment groups (n=8 each). Postischemic neurological deficits and infarct volume were determined 24 h after stroke-inducing surgery. Significant reductions in infarct volume (total and cortical) were found in group 2 (fluvoxamine 20 mg/kg given 6 h before and immediately after ischemic onset) and group 3 (fluvoxamine given immediately after ischemic onset and 2 h later) compared with controls. Fluvoxamine induced significant amelioration of sensorimotor dysfunction, as indicated by the scores of forelimb and hindlimb placing tests. Moreover, NE-100, a selective sigma-1 receptor antagonist, completely blocked the neuroprotective effect of fluvoxamine. The present findings suggest that the sigma-1 receptor agonist fluvoxamine reduces infarct volume and ameliorates neurological impairment even on postischemic treatment. From the clinical viewpoint, fluvoxamine may be a promising new therapeutic approach for cerebral infarction.

Successful treatment of severe abulia with co-beneldopa.

Abulia is a disorder of the executive and frontal lobe function. It is characterised by severe psychomotor slowing that is not due to depressive illness or catatonic schizophrenia. Abulia is thought to be due to disruption of the meso-cortico-limbic dopaminergic system. Preliminary evidence suggests that patients with abulia may respond to treatment with dopaminergic drugs. We extend this evidence by reporting a significant and sustained functional improvement in a severely abulic patient after treatment with co-beneldopa (Madopar).

Effect of the p38 MAPK inhibitor SB-239063 on Lipopolysaccharide-induced psychomotor retardation and peripheral biomarker alterations in rats.

Lipopolysaccharide (LPS) administration in rats induces a characteristic syndrome termed 'sickness behavior', including profound changes on locomotor activity and circulating stress and inflammatory mediators. The aim of the present investigation was to evaluate whether the behavioral and the peripheral biomarker responses induced by LPS could be modified by acute treatment with the p38 mitogen-activated protein kinase inhibitor SB-239063. Male Sprague-Dawley rats were treated orally either with vehicle or SB-239063 (3, 10 and 30 mg/kg) 1h before an intraperitoneal injection of either saline or LPS 125 µg/kg. Two hours after LPS injection, rats were placed in a novel open field arena for locomotion assessment during both the light and dark periods. Inflammation and stress mediators were evaluated in plasma 2, 3, 5 or 14 h into the dark phase. Pre-treatment with SB-239063 significantly reversed the locomotor deficits induced by LPS injection. Interleukin (IL)-1ß, IL-6, IL-10, Granulocyte-Macrophage-Colony Stimulating Factor, Interferon-γ, and C-reactive-protein levels were increased significantly by LPS, but not when LPS was preceded by SB-239063 treatment. LPS significantly decreased growth-hormone and Prolactin, and this effect was attenuated by SB-239063. Tumor Necrosis Factor-α, Adrenocorticotropic Hormone and Corticosterone levels were significantly higher in LPS-treated rats and were not normalized by SB-239063. Thus, we demonstrate that acute treatment with SB-239063 may have ameliorating effects in early changes of LPS-induced sickness behavior and alteration in the peripheral cytokines/hormones. As such, our procedure may offer an opportunity to test the activity of novel anti-inflammatory compounds on specific symptoms of sickness associated with neuroimmune dysfunctions.

[Using psychostimulants in end-of-life patients with hypoactive delirium and cognitive disorders: A literature review]. / Utilisation des psychostimulants chez les patients en fin de vie atteints de delirium hypoactif et de troubles cognitifs : revue de la littérature.

OBJECTIVE: To review the research about psychostimulant effects on cognitive functions in end-of-life patients diagnosed with hypoactive delirium or cognitive disorders. METHOD: The MEDLINE (1966-March 2008), Embase (1974-March 2008), PsycINFO (1806-March 2008), IPA (1970-March 2008), CINAHL (1982-March 2008), ISI Web of Science (1945-March 2008), Current Contents (March 2007-March 2008), Access Medicine (2001-March 2008), and ProQuest Dissertations & Theses (1980-March 2008) databases were searched with keywords related to delirium, cognition, psychostimulants, and palliative care for French or English articles in a dementia-free and hyperactive delirium-free end-of-life population. Cognitive functions had to be assessed before and after initiation of the psychostimulant treatment. Moreover, treatment had to be initiated after the onset of cognitive impairments. RESULTS: A total of 173 studies were screened. Five studies on methylphenidate and 1 study on caffeine met inclusion criteria and were included in this review. Two studies were case reports, 2 were open-label trials, and 2 were double-blind, crossover randomized placebo-controlled trials. Three studies were conducted with hypoactive delirium patients and all studies were conducted in an advanced cancer patient population. CONCLUSIONS: The reviewed studies support the use of methylphenidate to improve end-of-life patient cognitive functions, particularly in the case of hypoactive delirium. Caffeine seems to have beneficial effects on psychomotor activity. Further well-designed studies are needed to consolidate these findings.

[Results with botulinum toxin in patients with esotropia and psychomotor deficit]. / Resultados con la aplicación de toxina botulínica en pacientes con endotropía y retraso psicomotor.

OBJECTIVE: We undertook this study to evaluate the results of the treatment with botulinum toxin in patients with esotropia and psychomotor delay. METHODS: Patients with esotropia and delayed psychomotor development, in rehabilitation therapy and without previous surgery were included. A complete ophthalmological and strabismological exploration was performed including cycloplegic refraction with atropine 1%. Botulinum toxin was applied under sedation in both internal recti. Results were evaluated 1 week, 1 month, 3 and 6 months and after 1 year of application. The reinjection was decided if a 25 DP esotropia or greater was obtained before 3 months of the first application. A good result was considered in patients who had 10 DP of deviation and variability <10 DP. RESULTS: Thirty two patients were included. There were 14 were women and 18 men with an age range from 5 months to 5 years (average 16.8 months). Eighteen patients had variability in the angle of deviation from 20 to 45 DP of esotropia and 14 without variability with an average of 39.12 DP. Thirteen patients were reinjected. A good result was obtained in 10 patients, fair in 17 patients and poor in 5 patients due to persistence of variability in four cases and 15 DP hypertropia in one. CONCLUSIONS: Application of botulinum toxin is a therapeutic alternative in patients with esotropia and psychomotor delay.

Resultados con la aplicación de toxina botulínica en pacientes con endotropía y retraso psicomotor / Results with botulinum toxin in patients with esotropia and psychomotor deficit

Objetivo: Evaluar los resultados del tratamiento con toxina botulínica en pacientes con endotropía y retraso psicomotor. Material y métodos: Se incluyeron pacientes con endotropía y retraso del desarrollo psicomotor menores de siete años, en tratamiento de rehabilitación y sin cirugía previa. Se les realizó exploración oftalmológica y estrabológica completa incluyendo cicloplejía con atropina a 1 %. Se aplicó toxina botulínica en ambos rectos internos bajo sedación y se evaluaron los resultados a la semana, al mes, a los tres y seis meses y al año. Se decidió reinyección si se obtuvo endotropía residual mayor de 25 dioptrías (dp) antes de los tres meses de la primera aplicación. Se consideró un buen resultado cuando hubo desviación dentro de las 10 dp y variabilidad menor o igual a 10 dp. Resultados: Se incluyeron 32 pacientes, 14 mujeres y 18 hombres. El rango de edad era de cinco meses a cinco años, con un promedio de 16.8 meses. Se encontraron 18 pacientes con variabilidad en el ángulo de desviación de 20 a 45 dp de endotropía y 14 sin variabilidad, con un promedio de 39.12 dp. Se reinyectaron 13 pacientes. En 10 pacientes hubo buen resultado, en 17 regular y en cinco malo. Los malos resultados fueron por persistencia de variabilidad importante en cuatro pacientes y en uno hipertropía mayor de 15 dp.Conclusiones: La aplicación de toxina botulínica es una alternativa terapéutica en pacientes con endotropía y retraso psicomotor.

OBJECTIVE: We undertook this study to evaluate the results of the treatment with botulinum toxin in patients with esotropia and psychomotor delay. METHODS: Patients with esotropia and delayed psychomotor development, in rehabilitation therapy and without previous surgery were included. A complete ophthalmological and strabismological exploration was performed including cycloplegic refraction with atropine 1%. Botulinum toxin was applied under sedation in both internal recti. Results were evaluated 1 week, 1 month, 3 and 6 months and after 1 year of application. The reinjection was decided if a 25 DP esotropia or greater was obtained before 3 months of the first application. A good result was considered in patients who had 10 DP of deviation and variability <10 DP. RESULTS: Thirty two patients were included. There were 14 were women and 18 men with an age range from 5 months to 5 years (average 16.8 months). Eighteen patients had variability in the angle of deviation from 20 to 45 DP of esotropia and 14 without variability with an average of 39.12 DP. Thirteen patients were reinjected. A good result was obtained in 10 patients, fair in 17 patients and poor in 5 patients due to persistence of variability in four cases and 15 DP hypertropia in one. CONCLUSIONS: Application of botulinum toxin is a therapeutic alternative in patients with esotropia and psychomotor delay.

Protective effect of granulocyte colony-stimulating factor on intracerebral hemorrhage in rat.

Granulocyte colony-stimulating factor (G-CSF) is a member of the cytokine family of growth factors that can protect the neurons from focal cerebral ischemia-induced injuries. The intracerebral hemorrhage (ICH) has been widely observed in the clinic; however, the protective effect of G-CSF on ICH is still elusive. We found in the present study that the intraperitoneal injection of G-CSF for 5 days could improve the ICH-induced neuronal behavioral impairment measured by limb placement assay. We also observed that injection of G-CSF could increase the number of stem cells in the specific zone of the hemorrhagic areas, demonstrated by the enhanced expression of nestin. Additionally, G-CSF could also promote the mobilization of circulating hemopoietic stem cells (HSCs) to the damaged brain areas and activate the astrocytes. Our results reveal that G-CSF is also protective for the ICH with the mechanisms involving proliferation of neural stem cells, the migration of HSCs and the activation of astrocytes.

Psychomotor functioning in chronic fatigue syndrome and major depressive disorder: a comparative study.

BACKGROUND: Studies comparing chronic fatigue syndrome (CFS) and major depressive disorder (MDD) reported similarities as well as differences between the two disorders. However, whereas psychomotor symptoms have been studied extensively in MDD, such research in CFS is more limited. Moreover, the few studies that compared cognitive and motor performance in MDD and CFS yielded inconsistent results. This study hence directly compares fine psychomotor functioning in both syndromes. METHODS: Thirty-eight patients diagnosed with CFS without a current major depressive episode (MDE), 32 MDD patients with a current MDE and 38 healthy controls performed two computerized copying tasks differing in complexity: a line-copying task that mainly requires motor effort and a figure-copying task requiring additional cognitive efforts. All participants were female. A multivariate general linear model was used to compute group differences. RESULT: Overall, both patient groups performed more slowly than the controls. Compared to CFS patients, patients with MDD needed significantly more time to copy the single lines but no such between-group performance difference was observed for the figure reproductions. In this latter copying task, the increasing complexity of the figures resulted in prolonged reaction times for all three participant groups with the effect being larger and the magnitude similar for the two patient groups. LIMITATIONS: All patients were female and most were on psychotropic medication. CONCLUSIONS: Both the MDD and CFS patients tested demonstrated an overall fine motor slowing, with the motor component being more affected in the MDD patients than in the CFS patients while both patient groups showed similar cognitive impairments.