ApoE MPTP

Parkinson's disease (PD) is characterized clinically by progressive motor dysfunction; overt parkinsonism is often preceded by prodromal symptoms including disturbances in the sleep-wake cycle. Up to 80% of patients with PD also develop dementia. In humans, there are three major apolipoprotein E isoforms: E2, E3, and E4. Increased rate of dementia in PD may be associated with E4 isoform. To better understand prodromal changes associated with E4, we exposed young (3-5 mo) male and female mice expressing E3 or E4 via targeted replacement to a subchronic dosage of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Its pathological features are dopaminergic neuronal death in the substantia nigra (SN), and significant reduction in dopamine (DA) content in the striatum. A large number of studies have found an increase in iron levels in PD patients and animal models, which suggested that brain iron metabolism dysfunction played a key role in the pathogenesis of PD. Lactoferrin (Lf) is a non-heme iron-binding glycoprotein belonging to the transferrin family, entering the cell membrane via a lactoferrin receptor-mediated pathway...

BACKGROUND/AIMS: We and other groups have demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (ALA-SDT) induces macrophage and foam cell apoptosis and stabilizes atherosclerosis (AS) plaques in animal models. Lymphocytes also play vital roles in the development of AS. The primary purpose of the present study was to investigate the effects of ALA-SDT on T helper (Th) cell fate and function, Th subset differentiation, and atherosclerotic lesion stability. METHODS: We utilized ALA-SDT on Western diet-fed apoE-/-mice in vivo and human Jurkat cells in vitro...

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson's disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD...

Lactoferrin (Lf) can bind to lactoferrin receptor (LfR), leading to iron transport through the plasma membrane. Besides iron transportation, Lf also has antioxidant and anti-inflammatory properties. In the brain, Lf is only synthesized by activated microglia. LfR is present in blood vessels and nigral dopaminergic neurons. Both nigral iron accumulation and microglia activation is believed to be involved in Parkinson's disease (PD), moreover, increased Lf and LfR in dopaminergic neurons were found in PD cases and MPTP-intoxicated mice...

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out...

Long term subthalamic nucleus (STN) high frequency stimulation (HFS) can improve most symptoms of Parkinson's disease (PD) patients and decrease the dosage of antiparkinsonian drug such as Madopar. The mechanism of STN HFS for PD still remains elusive. We hypothesize that the level of dopamine (DA) and its metabolites in the corpus striatum is increased after long term STN HFS. The aim of this study was to examine the DA and its metabolites in the extracellular space of corpus striatum in hemiparkinsonian monkeys during long term STN HFS...

With a view toward improving the neural bioavailability of administered dopaminergic compounds, including dopamine, synthetic efforts have been directed toward enhancing the brain bioavailability of these compounds by accessing cellular sugar transport systems with stereoselective dopaminergic drugs. While synthesis and chemistry of the resultant class of compounds has recently been described in US Patent No. 6,548,484, the associated biologic properties have not previously been reported. One member of this new class, IPX-750, is a pro-drug dopamine-gluconamine designed to retain stereospecificity of binding at: glucose transporters (GLUT 1/GLUT 3 and intestinal Na/glucose co-transporters SGLT1), dopamine transporter (DAT); and, dopaminergic receptors of the D1/D2 families...

In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D(1)-D(2) receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity...

cDNA microarray membranes comprising 1,200 different gene fragments have been employed to identify gene expression profile in MPTP-induced nigro striatal dopamine neurodegeneration and its protection with Rapomorphine. Both MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and R-apomorphine (R-APO) induced alterations in specific patterns of gene expression. MPTP altered the expression of 49 different genes involved in oxidative stress (oxidative stress-induced protein A 170, cytochrome P450 1A1 and Osp94), inflammation (cytotoxic cytokines, eg: IL-1, IL-6, TNF-alpha), protective cytokines (IL-10), glutamate receptors (NMDA but not AMPA receptors), neurotrophic factors (GDNF, EGF), nitric oxide synthase and transferrin receptor, as determined by microarray membrane hybridization...

R-Apomorphine (APO) the catechol-derived dopamine D1-D2 receptor agonist has been shown to be highly potent iron chelator and radical scavenger and inhibitor of membrane lipid peroxidation in vitro, in vivo and in cell culture employing PC12 cells. Its potency has been compared to the prototype iron chelator desferrioxamine (desferal), dopamine, nifedipine and dopamine D2 receptor agonists, bromocriptine, lisuride, pergolide and pramipexole. APO also inhibits brain and mitochondrial protein oxidation. In vivo APO protects against MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)- induced striatal dopaminergic neurodegeneration in C57 black mice with as low as 5 mg/kg...

OBJECTIVE: To observe the improved degree of pathogenic behaviour in monkey models of Parkinson's disease after transplantation of substantia nigra cells of human fetus. METHOD: 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to prepare monkey models of hemiparkinson's disease, i.e., early substantia nigra cells of human fetus were stereotaxically transplanted into PD monkey's behaviour for six months, using immuno-electromicroscopy to prove the transplanted survived neuron...

The effects of unilateral intracarotid administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in sheep were studied with the goal of producing a non-primate, large animal model of Parkinson's Disease. Adult female sheep were given an acute (over 30 min) or chronic (over 1 week) injection of MPTP (0.4-5.0 mg/kg) via the common carotid artery. Both methods produced parkinsonian-like behavior. Turning contralateral to the side of injection was induced by apomorphine (APO) in both groups. However, amphetamine (AMP) induced ipsilateral turning only in the chronic treatment group...

Four consecutive injections (s.c.) of apomorphine (Apo) were given to 5 parkinsonian monkeys after i.v. MPTP administration. The minimal effective dose (MED) of Apo was defined as that capable of reducing motor disability by 50% or more for a minimum period of 30 min. Repeated apomorphine injections were given with an interval of 30 min after the motor effect of the previous injection had worn off or with a separation of 3 h between injections. The doses used in different experiments were the MED (2.4 micrograms/kg), 4 MED and 8 MED...