Neuroprotection and immunomodulation in the gut of parkinsonian mice with a plasmalogen precursor.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It is typically associated with motor symptoms originating from the degeneration of nigrostriatal dopamine (DA) neurons. Early stages of PD have been associated with an alteration in DA production in intestinal DAergic neurons along with inflammation. Interestingly, decreased serum concentrations of ethanolamine plasmalogens (PlsEtn) have been reported in PD patients. Ethanolamine plasmalogens play a role in vesicular fusion and release during neurotransmission, and store neuroprotective polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and are strong anti-oxidants, highlighting areas of potential therapeutic interest. Docosahexaenoic acid is known to play important roles in both the central nervous and peripheral systems, in addition to acting as a precursor of several molecules that regulate the resolution of inflammation. The present study investigated the neuroprotective and anti-inflammatory properties of the DHA-containing PlsEtn precursor, PPI-1011, in the intestine of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Treatment with PPI-1011 prevented the MPTP-induced decrease in PlsEtn levels. In addition it prevented the loss of tyrosine hydroxylase (TH) expression and reduced the infiltration of macrophages in the myenteric plexus of MPTP-treated mice. The protective effects of PPI-1011 were observed regardless of whether it was administered pre- or post- MPTP treatment. These results suggest that PPI-1011 has neuroprotective and anti-inflammatory properties in the gut and indicate its potential utility as a treatment for both early and more advanced stages of PD.

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice.

BACKGROUND: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. METHODS: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. RESULTS: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. CONCLUSION: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

Estrogen receptors and gonadal steroids in vulnerability and protection of dopamine neurons in a mouse model of Parkinson's disease.

17ß-estradiol is well known to have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We investigated the neuroprotective contribution of estrogen receptors (ERα and ERß) against MPTP toxicity by examining the membrane dopamine (DA) transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH) in ER knock out (ERKO) C57Bl/6 male mice compared to their plasma steroid levels. A dose-response to MPTP comparing wild-type (WT) to ERKO mice was studied. WT mice were also compared to ERKO mice pretreated with 17ß-estradiol alone and with MPTP. Specific radioligand binding autoradiography and in situ hybridization for DAT, VMAT2 and TH were assayed in the striatum and the substantia nigra (SN). Intact ERKOß mice had both striatal transporters levels lower than WT and ERKOα mice. MPTP caused a dose-dependent loss of both striatal transporters that correlated with striatal DA concentrations. Compared to WT and ERKOß mice, ERKOα mice DAT, VMAT2 and TH were affected at lower MPTP doses. In the striatum and SN, ERKOα mice were more vulnerable and 17ß-estradiol protected against MPTP toxicity only in WT mice. ERKOα mice blood plasma had higher levels of testosterone, dihydrotestosterone and 3ß-diol compared to the plasma of WT and ERKOß mice. 17ß-estradiol treatment increased estradiol plasma levels in all genotypes. Striatal DA concentrations and SN TH mRNA correlated inversely with plasma testosterone and 3ß-diol levels. Hence, in male mice the lack of ERα or ERß altered their basal plasma steroid levels and both striatal DA transporters as well as their susceptibility to MPTP toxicity.

Estrogen and SERM neuroprotection in animal models of Parkinson's disease.

A higher prevalence and incidence of Parkinson disease (PD) is observed in men and beneficial motor effects of estrogens are observed in parkinsonian women. Lesion of the dopamine (DA) nigrostriatal pathway in animals with 1-methyl 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) provides a model of PD and this is based on its use in humans as side-product of a drug abuse. Presently treatment of PD is mainly symptomatic. The MPTP mouse is used to study the neuroprotective roles of estrogenic drugs on the DA system. Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone. An estrogen receptor agonist PPT and the selective estrogen receptor modulator raloxifene are also neuroprotective. Striatal DA neurons of estrogen receptor alpha knockout mice are more susceptible to MPTP toxicity than wild-type mice and neuroprotection by estradiol is associated with the activation of the PI3-K pathway involving Akt, GSK3beta, Bcl2 and BAD.

Role of estrogen receptors in neuroprotection by estradiol against MPTP toxicity.

Estradiol protects against striatal dopamine terminal loss caused by the neurotoxin MPTP in mice. This effect of estradiol is thought to be mediated by an interaction with estrogen receptors (ER), of which there are two: ERalpha and ERbeta. In the present study, the role of these two ERs in MPTP toxicity and its neuroprotection by estradiol was investigated using ER knock out mice (ERKO). MPTP (7, 9, or 11 mg/kg administered four times at 2h intervals) caused a dose-dependent decrease in striatal dopamine and dopamine metabolite DOPAC concentrations in wild type (WT) mice. The degree of dopamine and DOPAC depletion after MPTP was greater in the ERKOalpha mice than WT mice, whereas the ERKObeta mice exhibited no change in MPTP sensitivity. ERKObeta mice showed a lower DA turnover than WT and ERKOalpha mice. WT, ERKOalpha and ERKObeta mice were also treated for 10 days with exogenous estradiol and on day 5 of treatment were challenged with MPTP (9 mg/kg administered four times at 2h intervals). In the WT mice, estradiol partially prevented the MPTP-induced decrease in striatal dopamine and DOPAC concentrations. However, estradiol treatment was without significant neuroprotective effects in the ERKOalpha and ERKObeta mice. These results show a greater susceptibility to MPTP toxicity of ERKOalpha mice compared to WT and ERKObeta mice and a role for both ER receptors in striatal DA neuroprotection.