Precise Measurement of Differential Cross Sections of the Σ

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470

Neuroprotective properties of 17beta-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice.

Previous work from our laboratory showed prevention of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced dopamine depletion in striatum of C57Bl/6 mice by 17beta-estradiol, progesterone, and raloxifene, whereas 17alpha-estradiol had no effect. The present study investigated the mechanism by which these compounds exert their neuroprotective activity. The hormonal effect on the dopamine transporter (DAT) was examined to probe the integrity of dopamine neurons and glutamate receptors in order to find a possible excitotoxic mechanism. Drugs were injected daily for 5 days before MPTP (four injections, 15 mg/kg ip at 2-h intervals) and drug treatment continued for 5 more days. MPTP induced a decrease of striatal DAT-specific binding (50% of control) and DAT mRNA in the substantia nigra (20% of control), suggesting that loss of neuronal nerve terminals was more extensive than cell bodies. This MPTP-induced decrease of striatal [(125)I]RTI-121 specific binding was prevented by 17beta-estradiol (2 microg/day), progesterone (2 microg/day), or raloxifene (5 mg/kg/day) but not by 17alpha-estradiol (2 microg/day) or raloxifene (1 mg/kg/day). No treatment completely reversed the decreased levels of DAT mRNA in the substantia nigra. Striatal [(125)I]RTI-121 specific binding was positively correlated with dopamine concentrations in intact, saline, or hormone-treated MPTP mice. Striatal NMDA-sensitive [(3)H]glutamate or [(3)H]AMPA specific binding remained unchanged in intact, saline, or hormone-treated MPTP mice, suggesting the unlikely implication of changes of glutamate receptors in an excitotoxic mechanism. These results show a stereospecific neuroprotection by 17beta-estradiol of MPTP neurotoxicity, which is also observed with progesterone or raloxifene treatment. The present paradigm modeled early DA nerve cell damage and was responsive to hormones.

Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice.

Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17beta- and 17alpha-estradiol treatment (1 microg twice daily 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neurotoxin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrations and its metabolites dihydroxyphenylacetic acid and homovanillic acid measured by HPLC in MPTP mice that received 17beta-estradiol were comparable to control animals, whereas MPTP mice treated with saline or 17alpha-estradiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations remained unchanged after MPTP and treatments with steroids. Striatal [(3)H]GBR 12935 binding autoradiography to the dopamine transporter was as extensively decreased and correlated with dopamine depletion in MPTP mice, whereas this transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [(3)H]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significantly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting against the extensive loss of dopamine terminals and moderate cell body loss.

Drugs with estrogen-like potency and brain activity: potential therapeutic application for the CNS.

Numerous reports, ranging from molecular investigations to clinical studies, demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. Alterations of dopaminergic, cholinergic, GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated mechanisms have been consistently established. Moreover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous system (CNS) cells implicated in the etiology of neurodegenerative disorders such as Alzheimer s (AD) and Parkinson s (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been documented implicating classical nuclear estrogen receptors as well as possible estrogen membrane receptors, antioxidant activity of steroids, their effect on fluidity as well as on antiapoptotic proteins and growth factors. Selective estrogen receptor modulators (SERMs) have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have the same beneficial effect as estrogen in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The finding of beneficial side effects of SERMs in the CNS might improve their risk-benefit ratio in traditional indications. In this review, we will survey schizophrenia and depression as examples of mental diseases and AD and PD as neurodegenerative diseases. We will review brain effects of estrogens, steroids possibly acting as pro-drugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) and present novel findings with SERMs. Drugs with estrogen activity in the brain may have therapeutic potential either by modulating brain neurotransmitter transmission or through neuroprotective activity.

CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a common disease of the central nervous system characterized by myelin loss and progressive neurological dysfunction. An underlying genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure. Full-genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS. Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS gene(s) of modest effect. Encoded here are two chemokine receptors, CCR5 and CCR2B. We examined the chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed genetic analyses of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage- and association-based tests. No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyses (ASPEX), and association testing (sib-TDT) for each locus were also not significant. However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects). Thus, chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate inflammatory demyelination.

Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice.

The activity of steroids was studied in 1-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned retired breeder C57BL/6 male mice as a model of Parkinson's disease. Steroids were injected daily for 5 days before MPTP (4 injections, 15 mg/kg i.p., at 2 h intervals) and hormonal treatment continued for 5 more days. Mice that received 17beta-estradiol or progesterone or raloxifene (a selective estrogen receptor modulator) and MPTP had striatal concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) similar to those in control animals, whereas mice that received MPTP alone or with 17alpha-estradiol (the isomer with weak estrogenic activity) had an extensive decrease of DA and its metabolites. These results suggest stereospecific prevention of MPTP-induced dopamine loss by 17beta-estradiol, which is also observed with progesterone and raloxifene.

Effect of dehydroepiandrosterone and its sulfate and fatty acid ester derivatives on rat brain membranes.

The effects of dehydroepiandrosterone (DHEA) as well as its sulfate and fatty acid ester derivatives on rat brain membrane fluidity was investigated by fluorescence depolarization of a lipid probe 1,6-diphenyl-1,3,5-hexatriene and compared to its effect on phospholipid conformation investigated by Fourier transform infrared spectroscopy. In rat brain, membrane fluidity varied rostro-caudally, the frontal cortex showing the highest fluidity compared to the hypothalamus, hippocampus, striatum, thalamus, and hindbrain. As previously reported, it was observed that cholesteryl hemisuccinate and stearic acid rigidify striatal membrane whereas linoleic acid and L-alpha-phosphatidylcholine increase the membrane fluidity. Striatal fluidity was increased in vitro with increasing concentrations of DHEA, this effect was greater with the DHEA fatty acid ester derivatives (DHEA-L), DHEA-undecanoate, and DHEA-stearate, whereas no effect was observed with DHEA-sulfate (DHEA-S). In the frontal cortex only the two DHEA-L derivatives increased membrane fluidity, whereas DHEA and DHEA-S were without effect. The effect of DHEA-L on synthetic dimyristoylphosphatidylcholine-d54 phospholipid membranes indicates a disordering effect of DHEA-undecanoate and DHEA-stearate as reflected by increased trans-gauche isomerization of the acyl chains of the lipid. Hence, DHEA-L increase the disorder and/or fluidity of brain membranes; interestingly, these compounds are abundant in the brain where they are generally considered as storage compounds that slowly release the active unconjugated steroid hormone.