BackgroundSynucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy.MethodsWe determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches.ResultsAfter 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.ConclusionTaken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.

Rationale-Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative and anticonvulsant effects, and their actions at different modulatory sites on GABA A receptors might confer differences in adverse effects.Objectives-This study used drug discrimination to compare discriminative stimuli produced by positive GABA A modulators that vary in their site of action on GABA A receptors.Methods-Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation.Results-Pregnanolone, midazolam and flunitrazepam produced ≥80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ≥80% drug-lever responding in all rats discriminating pregnanolone and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity and pA 2 values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone.Conclusions-The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines. Keywordsregnanolone; midazolam; flumazenil; drug discrimination; Schild analyses; rats γ-Aminobutyric acid A (GABA A ) receptors are important therapeutic targets, and drugs that act at benzodiazepine binding sites on GABA A receptors are used clinically. Despite their effectiveness and large margin of safety, there are adverse effects associated with the clinical use of benzodiazepines, including the development of tolerance and dependence (Lader 2008; Cloos and Ferreira 2008). Treatment might be improved by developing drugs that retain the therapeutic effects of benzodiazepines while reducing their adverse effects. One strategy for identifying potential replacements for benzodiazepines is to target different Given the differences between benzodiazepines and neuroactive steroids, their acute behavioral effects might also not be identical. One procedure in which differences in the acute effects of benzodiazepines and neuroactive steroids have been observed is drug discrimination. Drugs acting at benzodiazepine, barbiturate or neuroactive steroid binding sites have been established as discriminative stimuli, and generally, they share discriminative stimulus effects (e.g., de la Garza and Johanson 1987;Ator et al. 1993;McMahon et a...

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Considerable evidence suggests that oxidative stress plays a role in the pathogenesis of Parkinson’s disease (PD), the most prevalent neurodegenerative movement disorder. Reduced expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), enzymes that function to detoxify aldehydes and hydroxyl radicals, respectively, has been reported in the substantia nigra of patients who died with PD. To determine whether deficiency in these two genes contributes to the pathogenesis of PD, mice were generated with homozygous null mutations of both Aldh1a1 (the murine homolog of ALDH1) and Gpx1 genes [knockout (KO) mice]. At 6 and 18 months of age, KO mice showed a significantly decreased latency to fall in the automated accelerating rotarod test and increased time to complete the pole test opamine levels were not altered; however, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were significantly reduced at 18 months of age. Proteins adducted with 4-hydroxynonenal, the end-product of lipid peroxidation, were increased in the. midbrain and striatum of KO mice at 6 and 18 months. In conclusion, dual mutations in Gpx1 and Aldh1a1 genes are associated with motor deficits and increased lipid peroxidation in adult mice.