Seema Gulyani

Insulin resistance and exendin-4 treatment for multiple system atrophy.

See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimers disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.

Up-regulation of striatal adenosine A2A receptors with iron deficiency in rats. Effects on locomotion and cortico-striatal neurotransmission.

Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS.

Sleep Medicine Pharmacotherapeutics Overview: Today, Tomorrow, and the Future (Part 1: Insomnia and Circadian Rhythm Disorders)

Over the past 10 years, significant strides have been made in the understanding, development, and availability of sleep disorder therapeutics. In this review series, we discuss the current evidence surrounding the mechanisms of actions, indications, efficacy, and adverse side effects associated with the available armamentarium of sleep over-the-counter and pharmacotherapeutics. This article is the first of a two-part series that covers the therapeutics for insomnia and circadian rhythm disorders.

Diminished iron concentrations increase adenosine A2A receptor levels in mouse striatum and cultured human neuroblastoma cells

Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D(2) receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A(2A) (A(2A)R) but not A(1) receptor (A(1)R) compared to mice on a normal diet. Between two inbred murine strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A(2A)R density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A(2A)R. In these cells, A(2A)R agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A(2A)R. A significant correlation (r(2)=0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A(2A)R protein density. In conclusion, the A(2A)R is increased across different iron-insufficient conditions. The relation between A(2A)R and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.

In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine.

Dopaminergic drugs have been used as the first-line treatment for restless legs syndrome (RLS) for many years and are considered to be, at least over the short-term, effective and safe. However, the main long-term complication of dopaminergic treatment is augmentation, which is an overall increase in symptom severity and intensity, with symptoms starting earlier in the afternoon and expanding to previously unaffected parts of the body. Augmentation is a common complication, with prevalence rates of nearly 50%, and is a common cause of treatment failure. Furthermore, augmentation occurs almost exclusively during treatment with dopaminergic drugs. Due to its frequency, there is a strong clinical need for treatment alternatives to dopaminergic drugs. Moreover, recent treatment guidelines recommend that treatment be initiated, whenever possible, with non-dopaminergic drugs (ie, α2δ ligands). Alternative treatments such as intravenous iron preparations directly address iron deficiency, as well as the consequences of iron deficiency in regard to glutamate and adenosine. This article also reviews current knowledge supporting an involvement of glutamatergic and adenosinergic neurotransmission in the pathophysiology of RLS, and explores the potential development of drugs acting on both systems.

Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome.

Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D2 receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron-deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radioligand binding saturation experiments in rat brain tissue) of adenosine A1 receptors (A1R) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A2A receptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for A1R downregulation in the PLMS and hyperarousal in RLS.

A step out of the dark: improving the sleep medicine knowledge of trainees.

OBJECTIVE Over 40-million Americans are undiagnosed, misdiagnosed, or untreated for sleep disorders. Despite the growing need to integrate sleep medicine knowledge into the medical education curriculum, educational leaders have struggled to incorporate contemporary medical topics such as sleep medicine into the already packed curricula. We set out to examine the efficacy of an online, self-paced, sleep medicine learning module as an educational tool for medical students. METHODS We studied 87 Johns Hopkins medical students. Participants were randomly assigned to the sham module (SM, n=40) or learning module (LM, n=47). The efficacy of the tool was assessed based on changes in performance (pre- and post-module completion) on a validated sleep knowledge questionnaire (the Dartmouth Sleep Knowledge and Attitude Survey). RESULTS Improvement in overall sleep knowledge, as measured by the Dartmouth Sleep Knowledge and Attitude Survey, was significantly higher in the LM group compared to the SM group (F(1,84)=9.71, p<.01, η(2)=0.10). Although the SM groups improvement was significantly lower than the LM group, within-subject comparisons did show improvement from their pre- to post-assessment scores as well. CONCLUSION A self-paced learning module is an effective educational tool for delivering sleep medicine knowledge to medical students.

Sleep Medicine Pharmacotherapeutics Overview: Today, Tomorrow, and the Future (Part 2: Hypersomnia, Parasomnia, and Movement Disorders)

Over the past 10 years, significant strides have been made in therapeutics for sleep disorders. In this second installment of a two-part review series, we discuss the current evidence surrounding the mechanisms of actions, indications, efficacy, and adverse side effects associated with the current over-the-counter and pharmacotherapeutics for hypersomnia, parasomnias, and movement disorders of sleep.

Role of Striatal A2A Receptor Subpopulations in Neurological Disorders

A very significant density of adenosine A2A receptors (A2AR) is present in the striatum, where they are preferentially localized postsynaptically in enkephalinergic-GABAergic-medium spiny neurons (enkephalinergic MSN). In this localization, different subpopulations of A2AR with different functions exist. Their differential function seems to depend mostly on their ability to form heteromers with other G-protein-coupled receptors, such as dopamine D2, cannabinoid CB1 and glutamate mGlu5 receptors. Furthermore, striatal A2AR are also localized presynaptically, in corticostriatal glutamatergic terminals that contact dynorphinergic-GABAergic-medium spiny neurons (dynorphinergic MSN). These presynaptic A2AR heteromerize with A1 receptors and their activation facilitates glutamate release. Pharmacological tools are becoming available that allow the functional evaluation of some of these different subpopulations of A2AR, which can therefore provide selective targets for drug development in different basal ganglia disorders. In fact, alterations in the function of different A2AR subpopulations have recently been observed in Parkinson’s disease and in animal models of Huntington disease and Restless Legs Syndrome.

Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel

ABSTRACT Objective: Identify biomarkers in peripheral blood that relate to chronic post-concussive and behavioural symptoms following traumatic brain injuries (TBIs) to ultimately improve clinical management. Research design: We compared military personnel with mild TBIs (mTBIs) (n = 42) to those without TBIs (n = 22) in concentrations of tau, amyloid-beta (Aβ42) and cytokines (tumour necrosis factor alpha (TNFα, interleukin (IL)-6 and -10) in neuronal-derived exosomes from the peripheral blood. We utilized nanosight technology coupled with ultra-sensitivity immunoassay methods. We also examined the impact of post-concussive and behavioural symptoms including depression and post-traumatic stress disorder (PTSD) on these neuronal-derived markers. Results: We report that concentrations of exosomal tau (F1, 62 = 10.50), Aβ42 (F1, 61 = 5.32) and IL-10 (F1, 59 = 4.32) were elevated in the mTBI group compared to the controls. Within the mTBI group, regression models show that post-concussive symptoms were most related to exosomal tau elevations, whereas exosomal IL-10 levels were related to PTSD symptoms. Conclusions: These findings suggest that chronic post-concussive symptoms following an mTBI relate to altered exosomal activity, and that greater tau pathology may underlie chronic post-concussive symptoms that develop following mTBIs. It also suggests that central inflammatory activity contributes to PTSD symptoms following an mTBI, providing necessary insights into the role of inflammation in chronic PTSD symptoms.