Calcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine.

The present experiments were designed to examine the ability of calcitriol to protect against methamphetamine (METH)-induced reductions in striatal serotonin (5-HT) release and content. Male Fischer-344 rats were administered vehicle or calcitriol (0.3, 1.

PINK1 deficiency is associated with increased deficits of adult hippocampal neurogenesis and lowers the threshold for stress-induced depression in mice.

Parkinson's disease (PD) is characterized by motor impairments and several non-motor features, including frequent depression and anxiety. Stress-induced deficits of adult hippocampal neurogenesis (AHN) have been linked with abnormal affective behavior in animals. It has been speculated that AHN defects may contribute to affective symptoms in PD, but this hypothesis remains insufficiently tested in animal models.

Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques.

Background: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed.

New Method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques.

Vegetation dynamics associated with changes in atmospheric nitrogen deposition and climate in hardwood forests of Shenandoah and Great Smoky Mountains National Parks, USA.

Ecological effects of atmospheric nitrogen (N) and sulfur (S) deposition on two hardwood forest sites in the eastern United States were simulated in the context of a changing climate using the dynamic coupled biogeochemical/ecological model chain ForSAFE-Veg. The sites are a mixed oak forest in Shenandoah National Park, Virginia (Piney River) and a mixed oak-sugar maple forest in Great Smoky Mountains National Park, Tennessee (Cosby Creek). The sites have received relatively high levels of both S and N deposition and the climate has warmed over the past half century or longer.

Reduced ability of calcitriol to promote augmented dopamine release in the lesioned striatum of aged rats.

Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Previous studies, carried out in young adult rats, have shown that calcitriol, the active metabolite of vitamin D, can be neuroprotective in 6-hydroxydopamine (6-OHDA) models of PD. However, as PD usually affects older individuals, the ability of calcitriol to promote dopaminergic recovery was examined in lesioned young adult (4 month old), middle-aged (14 month old) and aged (22 month old) rats.

Pioglitazone Attenuates Neuroinflammation and Promotes Dopaminergic Neuronal Survival in the Nigrostriatal System of Rats after Diffuse Brain Injury.

Increasing evidence suggests that traumatic brain injury (TBI) may raise the risk of developing late-onset Parkinson's disease (PD). Recently, the peroxisome proliferation-activated receptor gamma (PPARγ) agonist pioglitazone has been demonstrated to be neuroprotective in animal models of neurodegeneration. The present study investigates the vulnerability of the nigrostriatal system after TBI, and intervention with pioglitazone treatment.

Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease.

Background: To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson's disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed.

New Method: We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD.

Results: Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300μg, suggestive of a stimulative effect of the dopaminergic system.

Designer receptors enhance memory in a mouse model of Down syndrome.

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s.

Age and lesion-induced increases of GDNF transgene expression in brain following intracerebral injections of DNA nanoparticles.

In previous studies that used compacted DNA nanoparticles (DNP) to transfect cells in the brain, we observed higher transgene expression in the denervated striatum when compared to transgene expression in the intact striatum. We also observed that long-term transgene expression occurred in astrocytes as well as neurons. Based on these findings, we hypothesized that the higher transgene expression observed in the denervated striatum may be a function of increased gliosis.

Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats.

Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain.

Dynamic changes in dopamine neuron function after DNSP-11 treatment: effects in vivo and increased ERK 1/2 phosphorylation in vitro.

Glial cell-line derived neurotrophic factor (GDNF) has demonstrated robust effects on dopamine (DA) neuron function and survival. A post-translational processing model of the human GDNF proprotein theorizes the formation of smaller, amidated peptide(s) from the proregion that exhibit neurobiological function, including an 11-amino-acid peptide named dopamine neuron stimulating peptide-11 (DNSP-11). A single treatment of DNSP-11 was delivered to the substantia nigra in the rat to investigate effects on DA-neuron function.

Evoked dopamine overflow is augmented in the striatum of calcitriol treated rats.

Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These actions include reducing the severity of some central nervous system lesions, possibly by upregulating trophic factors such as glial cell line-derived neurotrophic factor (GDNF). GDNF has substantial effects on the nigrostriatal dopamine (DA) system of young adult, aged and lesioned animals.

Neurturin protects against 6-hydroxydopamine-induced reductions in evoked dopamine overflow in rat striatum.

Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has substantial effects on normal and lesioned nigrostriatal dopamine systems. However, its ability to protect against toxin-induced loss of striatal dopamine release has not been previously reported. The goal of the present study was to determine if NTN could protect against 6-hydroxydopamine (6-OHDA)-induced reductions in striatal dopamine overflow and tissue levels of dopamine and to compare the effects of NTN with those of GDNF.

Neurturin effects on nigrostriatal dopamine release and content: comparison with GDNF.

Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family; and, while GDNF has been shown to increase dopamine (DA) release in normal animals, the ability of NTN to alter DA release has not been previously reported. The purpose of the present study was to determine if NTN could alter striatal DA release, and to compare the effects of NTN to GDNF. Male Fischer-344 rats were given a single injection of vehicle or 5 microg NTN or GDNF into the right substantia nigra.

Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats.

Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene may contribute to the development of Parkinson's disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene.

Strain difference in the up-regulation of FGF-2 protein following a neurotoxic lesion of the nigrostriatal pathway.

Lesions of the nigrostriatal pathway are known to induce a compensatory up-regulation of various neurotrophic factors. In this study we examined protein content of basic fibroblast growth factor (FGF-2) in tissue samples taken from the ventral midbrain and striatum at two different time points following a neurotoxic lesion of the nigrostriatal pathway in two different rat strains, the outbred Sprague-Dawley (SD) and inbred F344 9 Brown Norway F1 hybrid (F344BNF1). Despite both rat strains having comparable lesions of the nigrostriatal pathway, we observed a difference in the temporal up-regulation of FGF-2 in ventral midbrain samples taken from the side ipsilateral to the lesion.

Striatal neuroinflammation promotes Parkinsonism in rats.

Background: Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.

Intrastriatal lipopolysaccharide injection induces parkinsonism in C57/B6 mice.

A role for inflammation has been hypothesized in the etiology and progression of Parkinson's disease (PD). In this study, we generated, characterized, and validated the first progressive PD-related mouse model (C57/B6) with intrastriatal injection of lipopolysaccharide (LPS). We showed progressive and specific dopaminergic neurodegeneration in the substantia nigra, which is accompanied by striatal dopamine depletion and progressive behavioral impairment, which was alleviated by the use of the PD drug L-Dopa.

Inflammation and age-related iron accumulation in F344 rats.

Evidence suggests chronic inflammation and iron accumulation may play a role in the pathogenesis of Parkinson's disease (PD) as inflammation and iron levels increase with age and appear in the disease pathology. It is hypothesized that an aggravated inflammatory response and iron accumulation, as a function of age, increase oxidative stress and participate in the pathogenesis of PD. Intracranial injection of the bacterial endotoxin, lipopolysaccharide (LPS), has been shown to induce microglia activation, oxidative stress, mitochondrial impairment, iron accumulation, and dopaminergic neurodegeneration within the substantia nigra.

Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity.

Objective: To analyze a cluster of 30 industrial coworkers with Parkinson's disease and parkinsonism subjected to long-term (8-33 years) chronic exposure to trichloroethylene.

Methods: Neurological evaluations were conducted on the 30 coworkers, including a general physical and neurological examination and the Unified Parkinson's Disease Rating Scale. In addition, fine motor speed was quantified and an occupational history survey was administered.

Fenbendazole treatment may influence lipopolysaccharide effects in rat brain.

In evaluating discrepant results between experiments in our laboratory, we collected data that challenge the notion that anthelminthic drugs like FBZ do not alter inflammatory responses. We found that FBZ significantly modulates inflammation in F344 rats intrastriatally injected with LPS. FBZ treatment of LPS-injected rats significantly increased weight loss, microglial activation, and dopamine loss; in addition, FBZ attenuated the LPS-induced loss of astrocytes.

Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration.

HIV-1 infection with concurrent methamphetamine (MA) abuse results in exacerbated neurodegenerative changes and rapid progression of a form of sub-cortical dementia termed HIV-1 associated dementia (HAD). A notable feature of HAD is the involvement of the dopaminergic system manifested as parkinsonian like movement abnormalities. The HIV-1 transactivator of transcription (Tat) protein is very often used in experimental studies trying to understand neurotoxic consequences of HIV-1 infection, since the pathophysiological changes induced by Tat mirrors, in part, the means by which HIV-1 infection of the nervous system results in neuronal damage.

Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system.

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration.