Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs.

Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.

A prototype stimulator system for noninvasive Low Intensity Focused Ultrasound delivery.

A prototype Low Intensity Focused Ultrasound (LIFU) stimulator system was developed to evaluate non-invasive neuromodulation in a large animal model. We conducted a feasibility study on a Göttingen minipig, demonstrating reversible, targeted transcranial neuromodulation. The hypothalamus of the minipig was repeatedly stimulated with LIFU which evoked temporally correlated increases in both heart rate and blood pressure.

Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model.

Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS.

A review of low-intensity focused ultrasound pulsation.

With the recent approval by the Food and Drug Administration (FDA) of Deep Brain Stimulation (DBS) for Parkinson's Disease, dystonia and obsessive compulsive disorder (OCD), vagus nerve stimulation (VNS) for epilepsy and depression, and repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression, neuromodulation has become increasingly relevant to clinical research. However, these techniques have significant drawbacks (eg, lack of special specificity and depth for the rTMS, and invasiveness and cumbersome maintenance for DBS). This article reviews the background, rationale, and pilot studies to date, using a new brain stimulation method-low-intensity focused ultrasound pulsation (LIFUP).

BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses.

Region-specific protein abundance changes in the brain of MPTP-induced Parkinson's disease mouse model.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify potential nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 nonredundant proteins with at least two unique peptides per protein.

Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge.

Bingeing is one pattern of high-dose methamphetamine (METH) abuse, which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats, we used a computer-controlled, intravenous METH procedure (dynamic infusion, DI) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life.

Identifying heritable brain phenotypes in an extended pedigree of vervet monkeys.

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes.

Regulation of Kaposi's sarcoma-associated herpesvirus reactivation by dopamine receptor-mediated signaling pathways.

Background: Kaposi's sarcoma-associated herpesvirus (KSHV) possesses two distinct life cycles, lytic replication and latency. An immediate early viral protein, Replication and transcription activator (RTA), is responsible for the virus switch from latency to active replication.

Methods: To identify cellular pathways that reactivate KSHV replication, an RTA-responsive viral early promoter, PAN, coupled with an enhanced green fluorescent protein (EGFP) reporter was delivered into a KSHV latently infected B cell line.

Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.

Purpose: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies.

Materials And Methods: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.

Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey. Laboratory investigation.

Object: Deep brain stimulation (DBS) has become an effective therapy for an increasing number of brain disorders. Recently demonstrated DBS of the posterior hypothalamus as a safe treatment for chronic intractable cluster headaches has drawn attention to this target, which is involved in the regulation of diverse autonomic functions and feeding behavior through complex integrative mechanisms. In this study, the authors assessed the feasibility of ventromedial hypothalamus (VMH) DBS in freely moving vervet monkeys to modulate food intake as a model for the potential treatment of eating disorders.

Mitochondrial dysfunction, oxidative stress, and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson's disease.

The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson's disease (PD) are not completely understood. Here, we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 86 proteins with significant abundance changes following neurotoxin treatment.

Methamphetamine increases basal ganglia iron to levels observed in aging.

Increases in basal ganglia iron are well documented for neurodegenerative diseases but have not been associated with methamphetamine (METH). In this study, vervet monkeys that received two doses of METH (2 mg/kg, intramuscularly, 6 h apart) showed at 1 month, iron increases in substantia nigra pars reticulata and globus pallidus, with concurrent increases of ferritin-immunoreactivity and decreases of tyrosine hydroxylase-immunoreactivity in substantia nigra. At 1.

Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey.

To elucidate the organization of the serotoninergic innervation within the orbitofrontal cortex (OFC), serotonin transporter (SERT) density was quantified by autoradiography using [(3)H]cyanoimipramine binding. In six adult vervet monkeys, 15 architectonic areas were delineated according to cytoarchitectonic (Nissl), myeloarchitectonic (Gallyas) and chemoarchitectonic (acetylcholinesterase) criteria to assess SERT distribution at two levels of organization: cortical area and cortical type. For cortical type, the 15 areas were evenly divided into three different categories primarily based upon the degree of granularization of layer IV: agranular, dysgranular, and granular.

Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys.

Methamphetamine blood concentrations in human abusers: application to pharmacokinetic modeling.

Characterization of methamphetamine's (METH) dose-dependent effects on brain neurochemistry may represent a critical component for better understanding the range of resultant behavioral pathologies. Most human studies, however, have assessed only the effects of long term, high dose METH abuse (e.g.

Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge.

A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.

Endogenously nitrated proteins in mouse brain: links to neurodegenerative disease.

Increased abundance of nitrotyrosine modifications of proteins have been documented in multiple pathologies in a variety of tissue types and play a role in the redox regulation of normal metabolism. To identify proteins sensitive to nitrating conditions in vivo, a comprehensive proteomic data set identifying 7792 proteins from a whole mouse brain, generated by LC/LC-MS/MS analyses, was used to identify nitrated proteins. This analysis resulted in the identification of 31 unique nitrotyrosine sites within 29 different proteins.

Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization.

The translational value of preclinical models of methamphetamine abuse depends in large part on the degree to which the drug regimens used in animals produce methamphetamine exposure patterns similar to those experienced by human methamphetamine abusers. To approximate one common form of methamphetamine abuse, we studied the effects of a schedule of intravenous methamphetamine administration in rats which included 2 weeks of progressively more frequent drug injections (0.125 mg/kg/injection) followed by 40 maintenance days during which animals received 40 daily injections (at 15-min intervals), with the dose gradually increasing (0.

Functional stereotactic radiosurgery involving a dedicated linear accelerator and gamma unit: a comparison study.

Object: The purpose of this work was to investigate the targeting and dosimetric characteristics of a linear accelerator (LINAC) system dedicated for stereotactic radiosurgery compared with those of a commercial gamma knife (GK) unit.

Methods: A phantom was rigidly affixed within a Leksell stereotactic frame and axial computerized tomography scans were obtained using an appropriate stereotactic localization device. Treatment plans were performed, film was inserted into a recessed area, and the phantom was positioned and treated according to each treatment plan.

Development and evaluation of an automated atlas-based image analysis method for microPET studies of the rat brain.

An automated method for placement of 3D rat brain atlas-derived volumes of interest (VOIs) onto PET studies has been designed and evaluated. VOIs representing major structures of the rat brain were defined on a set of digitized cryosectioned images of the rat brain. For VOI placement, each PET study was registered with a synthetic PET target constructed from the VOI template.

Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge.

The neurotoxic effects of methamphetamine (METH) have been characterized primarily from the study of high-dose binge regimens in rodents. However, this drug administration paradigm does not include a potentially important feature of stimulant abuse in humans, that is, the gradual escalation of stimulant doses that frequently occurs prior to high-dose exposure. We have argued that pretreatment with escalating doses (EDs) might significantly alter the neurotoxic profile produced by a single high-dose binge.

The fetal and neonatal brain protein neuronatin protects PC12 cells against certain types of toxic insult.

The protein neuronatin is expressed in the nervous system of the fetus and neonate at a much higher level than in the adult. Its function is unknown. As a result of variable splicing, neuronatin mRNA exists in two forms, alpha and beta.