Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used targeting generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in substantia nigra fiber densities dopamine levels striatum normal. However, DJ-1–/– hypolocomotion when subjected amphetamine challenge increased striatal denervation dopaminergic loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine....

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin damages the nigrostriatal dopaminergic pathway. Supporting pathogenic significance alterations findings general cdk inhibitor, flavopiridol, or dominant-negative cdk5, to lesser extent cdk2, attenuates loss...

The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement calcium-dependent proteases, calpains, loss mouse model PD. We show that administration N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase calpain-mediated proteolysis nigral vivo. Inhibition calpain using either inhibitor (MDL-28170) or adenovirus-mediated overexpression endogenous...

The effects of several stressors were assessed in inbred strains mice, BALB/cByJ and C57BL/6ByJ, thought to be differentially reactive stressors. Behavioral reactivity was greater mice with respect open-field emergence, step-down responding, response a predator (rat) or fox urine odor. Neurogenic insults (e.g., footshock, forced swim, restraint) systemic stressor (intraperitoneal interleukin-1beta treatment) likewise provoked rise plasma corticosterone the mice. Psychogenic novel exposure,...

Microglia are the primary immunocompetent cells that protect brain from environmental stressors, but can also be driven to release pro-inflammatory cytokines and induce a cytotoxic environment. Brain-derived neurotrophic factor (BDNF) is important for regulation of plasticity, synapse formation, general neuronal health. Yet, little known about how BDNF impacts microglial activity. We hypothesized would have direct modulatory effect on cortical (Postnatal Day 1-3: P1-3) microglia (Embryonic...

Parkinson’s disease (PD) is a progressive neurodegenerative affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it great importance to determine early neuronal changes that may contribute progression. Recent attention has focused on lipids and their role in pro- anti-apoptotic processes. However, information regarding lipid alterations animal models PD lacking. In this study, we utilized high performance liquid...

The current study investigated the immediate neurophysiological effects of different types massage in healthy adults using functional magnetic resonance imaging (fMRI). Much attention has been given to default mode network, a set brain regions showing greater activity resting state. These (i.e. insula, posterior and anterior cingulate, inferior parietal medial prefrontal cortices) have postulated be involved neural correlates consciousness, specifically arousal awareness. We posit that would...

Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which cells may contribute or protect against a depressive phenotype remain unknown. To delineate changes accompany behavior, we used astroglial-specific bacTRAP mice exposed to chronic variable stress...

Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease and many inflammatory processes. Thus, we assessed the role of LRRK2 context endotoxin (lipopolysaccharide, LPS)-induced inflammation substantia nigra together with environmental toxicant, paraquat, that has been PD. Here found ablation prevented loss dopaminergic neurons behavioral deficits (motor) induced by LPS priming followed paraquat exposure. The also provoked phenotypic shift LPS-primed microglia...

Depression is a chronic and debilitating condition with significant degree of relapse treatment resistance that could stem, at least in part, from disturbances neuroplasticity. This has led to an increased focus on strategies target brain derived neurotrophic factor (BDNF), synaptic plasticity adult neurogenesis. In the current study we aimed assess whether erythropoietin (EPO) would have antidepressant-like effects given its already established pro-trophic actions. particular, assessed EPO...

Abstract Low doses of lipopolysaccharide, tumour necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), or exposure to a stressor (restraint) increased plasma corticosterone levels. In animals pretreated with marked sensitization the response was evident upon subsequent TNF‐α, restraint, 1 day later. As well, sickness‐inducing effects TNF‐α and IL‐1β were markedly in mice lipopolysaccharide. The when second treatment administered after lipopolysaccharide administration, but not 28‐day...

The impact of psychological stressors on the progression motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many different environmental "hits", we were interested whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment toxicant, paraquat, which previously been linked PD. Our findings support contention paraquat itself acted as systemic stressor, with...

Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease (PD) and also thought to be fundamentally involved numerous immune functions. Thus, we assessed the role of LRRK2 context effects environmental toxicant, paraquat, that has been PD known affect inflammatory processes.Male knockout (KO) transgenic mice bearing G2019S mutation (aged 6-8 months) or their littermate controls were exposed paraquat (two times per week for 3 weeks), sickness measures,...

Abstract One of the main hallmarks Parkinson’s disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms component intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well an A53T mutant adenovirus to mimic conditions pathological protein in dopaminergic human derived SH-SY5Y neural cells. Since there evidence that mTOR pathway and glutamatergic signaling each influence aggregation, we also assessed impact inhibitor, rapamycin mGluR5...

Abstract The acoustic startle response, prepulse inhibition, fear‐potentiated and monoamine activity induced by either, a novel stimulus or cue previously paired with foot‐shock (fear‐conditioning), were assessed in rats selectively bred for differences amygdala excitability (Fast vs. Slow kindling epileptogenesis). Comorbid of anxiety, which dependent both on the rats' behavioural style kind stressor, also characterized these strains. In present investigation, exhibited greater reflex to...

A number of epidemiological and experimental studies have implicated the non-selective herbicide, paraquat, in development sporadic Parkinson's disease (PD). While preclinical research has focused mainly on elucidating nigrostriatal effects relatively little data are available concerning non-motor brain systems inflammatory immune processes (which been PD). Hence, present study, we sought to take a multi-system approach characterize influence paraquat upon extra-nigrostriatal regions, as...

Little is known of the age-dependent and long-term consequences low exposure levels herbicide dopaminergic toxicant, paraquat. Thus, we assessed dose-dependent effects paraquat using a typical short-term (3 week) procedure, followed by an assessment chronic (16 weeks) to very dose (1/10th what previously induced neuronal damage). Short term treatment dose-dependently deficits in locomotion, sucrose preference Y-maze performance. Chronic had different pattern that were also dependent upon age...

Abstract Parkinson’s disease (PD) is characterized by the formation of toxic, fibrillar form alpha-synuclein (α-Syn) protein aggregates in dopaminergic neurons. Accumulating evidence has shown a multifactorial interplay between intracellular calcium elevation and α-Syn dynamics. However, whether membrane depolarization regulates toxic remains unclear. To understand this better, we used an vitro preformed fibrils (PFF) model PD human neural cells. We demonstrated functional differentiated...

Combined cell and gene-based therapeutic strategies offer potential in the treatment of neurodegenerative psychiatric conditions that have been associated with structural brain disturbances. In present investigation, we used a novel virus-free re-programming method to generate induced pluripotent stem cells (iPSCs), then subsequently transformed these into neural which over-expressed derived neurotrophic factor (BDNF). Importantly, infusion iPSC (as replacement gene delivery tool) BDNF...

Parkinson's disease (PD) is a devastating age related neurodegenerative that believed to have lengthy prodromal state. It critical find methods harness compensatory recovery processes in order slow or prevent the eventual progression of clinical symptoms. The current perspective paper argues immune system signaling molecules represent such promising therapeutic approach. Two cytokines interest are granulocyte macrophage-colony stimulating factor (GM-CSF) and erythropoietin (EPO). These...