Sex-specific effects of prenatal valproic acid exposure on sociability and neuroinflammation: Relevance for susceptibility and resilience in autism.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with an incidence four times higher in boys than in girls. By analyzing the effect of sex in a mouse model of ASD, we were able to identify immune alterations that could underlie this sex bias. Pregnant mice were injected subcutaneously with 600 mg/kg of valproic acid (VPA) or saline at gestational day 12.5. Their male and female offspring were evaluated in a social interaction test at adulthood, and only male VPA mice showed reduced sociability levels and a lack of preference for the social stimulus over a novel object. We then analyzed the corticosterone (CORT) response to an inflammatory stimulus, as a measure of the hypothalamus-pituitary-adrenal (HPA) function, and the neuroinflammatory state in adult and young animals. Adult VPA males exhibited increased basal CORT levels, while VPA females showed levels comparable to controls. As male mice showed a blunted CORT response at PD21 when compared to female mice, we propose that this early dimorphism could explain the different effects of VPA on HPA function. In addition, prenatal VPA exposure resulted in altered astroglial and microglial cell density levels in the cerebellum and dentate gyrus of adult mice. These neuroinflammatory effects were more pronounced in females than males, and appeared at early developmental stages. Hence, these postnatal glial density differences could underlie the behavioral alterations observed in adulthood, when only males show a social deficit. Our work contributes to the understanding of biological mechanisms affected by VPA on male and female rodents and shed light on the study of possible resilience mechanisms in the female population and/or susceptibility to ASD in boys.

[Enhanced effect of guizhi plus Gegen Decoction on learning and memory disorder in LPS induced neuroinflammatory mice].

OBJECTIVE: To explore the potential effect of Guizhi plus Gegen Decoction (GGD) in improving learning and memory of lipopolysaccharides (LPS) induced neuroinflammatory mice and its possible mechanisms. METHODS: Totally 63 male ICR mice were randomly divided into 5 groups, i.e., the normal control (n = 13), the model group (n = 13), the low dose GGD group (n = 10), the high dose GGD group (n = 14), and the positive control group (n = 13). Mice were intraperitoneally injected with LPS (0.33 mg/kg) to induce Alzheimer's disease (AD) model. Mice in the high and the low dose GGD groups were administered with 12 g/kg or 6 g/kg by gastrogavage for 4 successive weeks. Mice in the control group were intraperitoneally injected with minocycline (50 mg/kg) for 3 days. By the end of treatment LPS were injected 4 h before behavior test each day, and then behavior test was conducted in mice of each group. Effect of GGD on learning and memory of AD mice was observed by using open field test, novel object recognition task, and Morris water maze. RESULTS: Open field test showed there was no statistical difference in the movement time and the movement distance among all groups (P > 0.05), suggesting that LPS and GGD had no effect on locomotor activities of mice. In novel object recognition test, AD mice spent significantly shorter time to explore novel object after they were induced by LPS (P < 0.05), while for AD mice in the low and high dose GGD groups, their capacities for exploration and memory were significantly improved (P < 0. 05, P < 0.01). Results of Morris water maze showed that AD mice exhibited increased escape latency (P < 0.05) and spent much less time in swimming across the original platform (both P < 0.05). However, AD mice in the low and high dose GGD groups had obvious shortened latency and increased time percentage for swimming (P < 0.05, P < 0.01). CONCLUSION: GGD possessed certain improvement in learning and memory disorder of LPS induced AD mice.

Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation.

Age is the principal nonmodifiable risk factor for stroke. Over the past 10 years, suitable models for stroke in aged rats have been established. At genetic and cellular level there are significant differences in behavioral, cytological and genomics responses to injury in old animals as compared with the young ones. Behaviorally, the aged rats have the capacity to recover after cortical infarcts albeit to a lower extent than the younger counterparts. Similarly, the increased vulnerability of the aged brain to stroke, together with a decreased interhemisphere synchrony after stroke, assessed by different experimental methods (MRI, fMRI, in vivo microscopy, EEG) leads to unfavorable recovery of physical and cognitive functions in aged people and may have a prognostic value for the recovery of stroke patients. Furthermore, in elderly, comorbidities like diabetes or arterial hypertension are associated with higher risk of stroke, increased mortality and disability, and poorer functional status and quality of life. Aging brain reacts strongly to ischemia-reperfusion injury with an early inflammatory response. The process of cellular senescence can be an important additional contributor to chronic post-stroke by creating a "primed" inflammatory environment in the brain. Overall, these pro-inflammatory reactions promote early scar formation associated with tissue fibrosis and reduce functional recovery. A better understanding of molecular factors and signaling pathways underlying the contribution of comorbidities to stroke-induced pathological sequelae, may be translated into successful treatment or prevention therapies for age-associated diseases which would improve lifespan and quality of life.

Insulin neuritis and diabetic cachectic neuropathy: a review.

Diabetic patients can be affected by a wide range of peripheral nerve disorders, the rarer of which are often poorly recognised and understood. "Insulin neuritis" or "treatment induced neuropathy" is a reversible disorder characterised by acute severe distal limb pain, peripheral nerve fibre damage and autonomic dysfunction, preceded by a period of rapid glycaemic control. The condition has been reported in both type 1 and type 2 diabetics treated with insulin or oral hypoglycaemic agents who typically have a history of poor glycaemic control. Pathogenesis of the condition and its associated pain is poorly understood, with proposed mechanisms including endoneurial ischaemia, hypoglycaemic microvascular neuronal damage and regenerating nerve firing. Pain can affect other areas including the trunk and abdomen, or be more generalised. "Diabetic neuropathic cachexia" is a rare disorder associated with poor diabetic control that presents with large amounts of unintentional weight loss associated with an acute symmetrical painful peripheral neuropathy without weakness. Pain is characteristically burning in nature with predominant lower limb involvement and allodynia. The disorder can also affect type 1 and type 2 diabetics and occur irrespective of the duration of their diabetes. Depression and in males, impotence, appear to be common, although other autonomic features can be present. Typically it has a monophasic course but has been reported to be recurrent. As with insulin neuritis, this condition is reversible over weeks to months after adequate diabetic control. For both disorders, the pain can be treatment resistant despite the use of multiple analgesics.

Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1-40 peptide in mice.

Alzheimer disease (AD) is the most common form of dementia in the elderly, and the neuro-pathological hallmarks of AD include neurofibrillary tangles (NFT), and deposition of beta-amyloid (Abeta) in extracellular plaques. In addition, chronic inflammation due to recruitment of activated glial cells to amyloid plaques are an invariant component in AD, and several studies have reported that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may provide a measure of protection against AD. In this report we have investigated whether phosphoinositide 3-kinase gamma (PI3Kgamma), which is important in inflammatory cell migration, plays a critical role in the neuro-inflammation, synaptic dysfunction, and cognitive deficits induced by intracerebroventricular injection of Abeta(1-40) in mice. We found that the selective inhibitor of PI3Kgamma, AS605240, was able to attenuate the Abeta(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, Abeta(1-40) activated macrophages treated with AS605240 or another PI3Kgamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was unaffected. Finally, AS605240 prevented Abeta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kgamma may represent a novel therapeutic target for treating AD patients.

HIV-related neurological syndromes reduce health-related quality of life.

BACKGROUND: Human immunodeficiency virus (HIV) infection frequently results in neurological complications but the impact of different neurological syndromes on patients' quality of life remains unknown. METHODS: We investigated health-related quality of life (HRQoL) parameters among HIV/Acquired Immune Deficiency Syndrome (AIDS) patients with and without neurological disease, including 11 dimensions of HRQoL within the Medical Outcomes Short-form Health Survey-HIV. RESULTS: Comparisons of sociodemographic and systemic clinical variables did not differ between HIV/AIDS patients with (n=94) and without (n=75) neurological disease. However, patients with neurological diseases exhibited significantly lower HRQoL scores compared to matched controls, which was most evident among HIV/AIDS patients with cognitive impairment and sensory neuropathy. Prospective analysis revealed diminishing HRQoL scores prior to neurological diagnosis followed by a progressive and sustained improvement in HRQoL scores after intervention over a 96-week period. CONCLUSIONS: These studies indicate that while HIV-related neurological diseases are associated with reduced HRQoL scores, enhanced neurological care has a positive impact on HIV/AIDS patients' overall well-being.

Motion perception in optic neuropathy.

We tested motion perception in 15 eyes of 13 patients with optic neuropathy. Eleven of the eyes had optic neuritis. The motion perception paradigm tested subjects' ability to discriminate the direction of a global coherent motion signal amid varying levels of background noise. The results showed defective motion processing in eight of the 15 eyes. This defect was not due to low visibility (poor spatial resolution), since 11 of the 15 eyes had Snellen acuities of 20/20 or better. Neither was impaired motion perception due to decreased luminance sensitivity, since attenuating the display signal by 2.1 log units (0.6 units more than the worst relative afferent pupillary defect in any patient) in five normal eyes had no effect. Motion perception and critical flicker fusion were independent of each other. Given proposals that both depend exclusively on the same M, or transient, channel, we had not predicted this double dissociation between flicker and motion perception.

Paralisia facial periférica, polineurite e doenças de Chagas crônica / Peripheral facial paralysis, polyneuritis and chronic Chagas' disease

É apresentado o caso de uma paciente com 42 anos, que exibiu paralisia facial periférica direita, polineurite sensitivo-motora e síndrome psicofuncional. Raciocínio clínico foi engendrado, permitindo a formulaçäo diagnóstica da forma nervosa crônica da doença de Chagas, sendo esta posteriormente confirmada pela investigaçäo laboratorial