Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-gamma in myelin from glia maturation factor-deficient mice

In this study we show the effect of anti-sulfatide (RmAb) antibodies and inflammatory cytokines, TNF-alpha and IFN-gamma in inducing myelin basic protein (MBP) degradation in myelin isolated from control wild type (WT) and glia maturation factor (GMF)-deficient (GMF-KO) mice. GMF was not detected in isolated myelin from WT and GMF-KO mice although it is present in brains of WT mice. Our results show that calcium-dependent neutral protease activity caused significantly elevated degradation of 18.5 and/or 17.5kDa isoforms of MBP in WT myelin treated with RmAb or IFN-gamma. In contrast, MBP degradation in isolated myelin from GMF-KO mice remained unaffected following treatment with RmAb, IFN-gamma, or GM-CSF. Neither the 14kDa isoform of MBP nor proteolipid protein (PLP) showed an elevated degradation compared to controls. A virtual absence of GM-CSF, TNF-alpha and IFN-gamma in GMF-KO brain compared to WT was also evident when the animals were challenged with MOG 35-55. Additionally, the myelin from GMF-KO mice showed difference in distribution of myelin oligodendrocyte glycoprotein (MOG) and beta-tubulin in a sucrose density gradient myelin-axolemmal fractions compared to WT. Taken together, our data suggests a role for GMF in the biochemical organization of myelin and thereby its effect on MBP degradation induced by RmAb and IFN-gamma.     

Low plasma antioxidant status in patients with epilepsy and the role of antiepileptic drugs on oxidative stress

Background:

Oxidative stress has been implicated in various disorders including epilepsy. We studied the antioxidant status in patients with epilepsy and aimed at determining whether there was any difference in the antioxidant levels between patients and controls, patients who are not on antiepileptic drugs (AEDs), and on treatment, between individual AEDs and patients on monotherapy and polytherapy.

Materials and Methods:

Antioxidant levels like catalase, glutathione peroxidase (GPx), vitamin E, glutathione (GSH), thiol group (SH), uric acid, and total antioxidant capacity (TAC) were compared between 100 patients with epilepsy and equal number of controls. Twenty-five patients who were not on AEDs were compared with patients on AEDs and the control group. Patients were divided into monotherapy and polytherapy group and antioxidant status was compared between the two groups and between individual drugs.

Results:

Catalase, SH, vitamin E, and TAC were significantly low in patients with epilepsy than those in the control group (P < 0.001). GSH and uric acid did not show any difference; GPx in patients was significantly higher than those in the control group There were no differences in the antioxidant levels between the treated and the untreated groups; however, it was lower in untreated patients than controls (P < 0.001), suggesting that AEDs do not modify the oxidative stress. Patients on Valproate (VPA) showed higher catalase and GPx levels. Catalase was higher in the monotherapy than polytherapy group (P < 0.04).

Conclusion:

Our study found significantly low levels of antioxidant in patients as compared to controls. AED did not influence the antioxidant status suggesting that seizures induce oxidative stress.     

Primary motor cortex long‐term plasticity in multiple system atrophy

In humans, intermittent and continuous theta‐burst stimulation (iTBS and cTBS) elicit long‐term changes in motor‐evoked potentials (MEPs) reflecting long‐term potentiation (LTP)‐ and depression (LTD)‐like plasticity in the primary motor cortex (M1). In this study, we used TBS to investigate M1 plasticity in patients with MSA. We also assessed whether responses to TBS reflect M1 excitability as tested by short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), short‐interval intracortical facilitation (SICF), and the input/output curves. We studied 20 patients with MSA and 20 healthy subjects (HS). Patients were clinically evaluated with the Unified Multiple System Atrophy Rating Scale. The left M1 was conditioned with TBS. Twenty MEPs were recorded from the right first dorsal interosseous muscle before TBS and 5, 15, and 30 minutes thereafter. In a subgroup of 10 patients, we also tested MEPs elicited by SICI, ICF, SICF, and input/output curves, before TBS. Between‐group analysis of variance showed that at all time points after iTBS MEPs increased, whereas after cTBS they decreased only in HS. In both subgroups tested, patients with predominant parkinsonian and cerebellar features, iTBS and cTBS left MEPs unchanged. MSA patients had reduced SICI, but normal ICF, SICF, and input/output curves. No correlation was found between patients' clinical features and responses to TBS and M1 excitability variables. These findings suggest impaired M1 plasticity in MSA. © 2013 International Parkinson and Movement Disorder Society     

Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D_2/3 receptors (D_2/3R) in humans in vivo. Our group has developed [¹¹C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D₃R. Thus, the use of [¹¹C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D_2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D₃R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [¹¹C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [¹¹C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D₂R-rich regions (caudate and putamen), mixed D_2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D₃R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [¹¹C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D₂R and D₃R in neuropsychiatric populations.