Bharathi S. Gadad

Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson's disease.

Parkinsons disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. Despite clinical and preclinical studies of neuroprotective strategies for PD, there is no effective treatment for preventing or slowing the progression of neurodegeneration. The inverse correlation between caffeine consumption and risk of PD suggests that caffeine may exert neuroprotection. Whether caffeine is neuroprotective in a chronic progressive model of PD has not been evaluated nor is it known if delayed caffeine treatment can stop DA neuronal loss. We show that a chronic unilateral intra-cerebroventricular infusion of 1-methyl-4-phenylpyridinium in the rat brain for 28 days produces a progressive loss of DA and tyrosine hydroxylase in the ipsilateral striatum and a loss of DA cell bodies and microglial activation in the ipsilateral substantia nigra. Chronic caffeine consumption prevented the degeneration of DA cell bodies in the substantia nigra. Importantly, neuroprotection was still apparent when caffeine was introduced after the onset of the neurodegenerative process. These results add to the clinical relevance for adenosine receptors as a disease-modifying drug target for PD.

The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4-phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD.

Neuropathology and Animal Models of Autism: Genetic and Environmental Factors

Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology.

Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial

OBJECTIVE Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed. METHOD Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n=51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n=55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants. RESULTS The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient=-0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient=0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1mg/L and Bupropion-SSRI for ≥1mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker. CONCLUSIONS Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder. Clinicaltrials.gov identifier: NCT00590863.

Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology.

Significance Autism is a childhood neurodevelopmental disorder affecting approximately 1 in 70 children in the United States. Some parents believe that thimerosal-containing vaccines and/or the measles, mumps, rubella (MMR) vaccine are involved in the etiology of autism. Here we gave nonhuman primate infants similar vaccines given to human infants to determine whether the animals exhibited behavioral and/or neuropathological changes characteristic of autism. No behavioral changes were observed in the vaccinated animals, nor were there neuropathological changes in the cerebellum, hippocampus, or amygdala. This study does not support the hypothesis that thimerosal-containing vaccines and/or the MMR vaccine play a role in the etiology of autism. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD.

Peripheral biomarkers of major depression and antidepressant treatment response: Current knowledge and future outlooks

BACKGROUND In recent years, we have accomplished a deeper understanding about the pathophysiology of major depressive disorder (MDD). Nevertheless, this improved comprehension has not translated to improved treatment outcome, as identification of specific biologic markers of disease may still be crucial to facilitate a more rapid, successful treatment. Ongoing research explores the importance of screening biomarkers using neuroimaging, neurophysiology, genomics, proteomics, and metabolomics measures. RESULTS In the present review, we highlight the biomarkers that are differentially expressed in MDD and treatment response and place a particular emphasis on the most recent progress in advancing technology which will continue the search for blood-based biomarkers. LIMITATIONS Due to space constraints, we are unable to detail all biomarker platforms, such as neurophysiological and neuroimaging markers, although their contributions are certainly applicable to a biomarker review and valuable to the field. CONCLUSIONS Although the search for reliable biomarkers of depression and/or treatment outcome is ongoing, the rapidly-expanding field of research along with promising new technologies may provide the foundation for identifying key factors which will ultimately help direct patients toward a quicker and more effective treatment for MDD.

Interleukin 17 selectively predicts better outcomes with bupropion-SSRI combination: Novel T cell biomarker for antidepressant medication selection

BACKGROUND Interleukin 17 (IL-17) is produced by highly inflammatory Th17 cells and has been implicated in pathophysiology of depression. IL-17 putatively disrupts the blood brain barrier and affects dopamine synthesis whereas dopamine has been shown to decrease Th17 cell-mediated immune response. Nevertheless, whether IL-17 can predict differential treatment outcome with antidepressants modulating dopaminergic transmission is unknown. METHODS IL-17 and other T cell and non-T cell markers (Th1, Th2 and non-T cell markers) were measured with the Bioplex Pro™ human cytokine 27-plex kit in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants who provided baseline plasma and were treated with either bupropion plus escitalopram (bupropion-SSRI), escitalopram plus placebo (SSRI monotherapy), or venlafaxine plus mirtazapine (n=166). Differential changes in symptom severity and side-effects based on levels of IL-17 and other T and non-T cell markers were tested using a treatment-arm-by-biomarker interaction in separate repeated measures mixed model analyses. Subsequent analyses stratified by treatment arm were conducted for those markers with a significant interaction. RESULTS There was a significant treatment-arm-by-IL-17 interaction for depression severity (p=0.037) but not for side-effects (p=0.28). Higher baseline IL-17 level was associated with greater reduction in depression severity (effect size=0.78, p=0.008) in the bupropion-SSRI but not the other two treatment arms. Other T and non-T cell markers were not associated with differential treatment outcomes. CONCLUSION Higher baseline levels of IL-17 are selectively associated with greater symptomatic reduction in depressed patients treated with bupropion-SSRI combination.

A search for blood biomarkers for autism: Peptoids

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication, and restricted, repetitive patterns of behavior. In order to identify individuals with ASD and initiate interventions at the earliest possible age, biomarkers for the disorder are desirable. Research findings have identified widespread changes in the immune system in children with autism, at both systemic and cellular levels. In an attempt to find candidate antibody biomarkers for ASD, highly complex libraries of peptoids (oligo-N-substituted glycines) were screened for compounds that preferentially bind IgG from boys with ASD over typically developing (TD) boys. Unexpectedly, many peptoids were identified that preferentially bound IgG from TD boys. One of these peptoids was studied further and found to bind significantly higher levels (>2-fold) of the IgG1 subtype in serum from TD boys (n = 60) compared to ASD boys (n = 74), as well as compared to older adult males (n = 53). Together these data suggest that ASD boys have reduced levels (>50%) of an IgG1 antibody, which resembles the level found normally with advanced age. In this discovery study, the ASD1 peptoid was 66% accurate in predicting ASD.

Platelet-Derived Growth Factor as an Antidepressant Treatment Selection Biomarker: Higher Levels Selectively Predict Better Outcomes with Bupropion-SSRI Combination

Abstract Background Platelet derived growth factor is integral to maintenance of blood brain barrier, increases in response to blood brain barrier disruption, and may reflect neuroinflammation. Based on previous reports of better outcomes with dopaminergic antidepressants in depressed patients with elevated inflammatory biomarkers, we hypothesize that elevated peripheral platelet derived growth factor levels can serve as a powerful biomarker for selecting dopaminergic antidepressants. Methods Platelet derived growth factor, basic fibroblast growth factor, and granulocyte colony stimulating factor were measured as part of Bioplex Pro human cytokine 27-plex kit in participants of the Combining Medications to Enhance Depression Outcomes trial who provided baseline plasma (n=166) and were treated with either bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine. Differential changes in overall symptom severity and anhedonia as well as side effects were tested with a treatment-arm-by-biomarker interaction in mixed model analyses. Effect of biomarkers with significant interaction was calculated in subsequent analyses stratified by treatment arm. Results There was a significant treatment-arm-by-platelet derived growth factor interaction for depression severity (P=.03) and anhedonia (P=.008) but not for side effects (P=.44). Higher baseline platelet derived growth factor level was associated with greater reduction in depression severity (effect size=0.71, P=.015) and anhedonia (effect size=0.66, P=.02) in the bupropion- selective serotonin reuptake inhibitor but not the other two treatment arms. There was no significant treatment-arm-by-biomarker interaction for both depression severity and side effects with the other two biomarkers. Conclusion As compared with selective serotonin reuptake inhibitor monotherapy or venlafaxine-plus-mirtazapine, bupropion-plus-escitalopram selectively improves anhedonia, which in turn results in improved overall depression severity in depressed patients with elevated platelet derived growth factor levels.

α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease: Critical Assessment and Modeling

Abstractα-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson’s disease (PD). The aggregation of α-synuclein is believed to be a critical event in the disease process. α-Synuclein is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. Therefore, it is classified as an “intrinsically disordered protein.” Recently, a debate has challenged the view on the intrinsically disordered behavior of α-synuclein in the cell. It has been proposed that α-synuclein is a stable tetramer with a low propensity for aggregation; however, its destabilization leads to protein misfolding and its aggregation kinetics. In our critical analysis, we discussed about major issues: (i) why α-synuclein conformational behavior does not fit into the normal secondary structural characteristics of proteins, (ii) potential amino acids involved in the complexity of misfolding in α-synuclein that leads to aggregation, and (iii) the role of metals in misfolding and aggregation. To evaluate the above critical issues, we developed bioinformatics models related to secondary and tertiary conformations, Ramachandran plot, free energy change, intrinsic disordered prediction, solvent accessibility, and FoldIndex pattern. To the best of our knowledge, this is a novel critical assessment to understand the misfolding biology of synuclein and its relevance to Parkinson’s disease.