Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease.

Previously, uridine pro-drug 2',3',5'-tri-O-acetyluridine (PN401) was shown to be protective in the mitochondrial complex II inhibitor 3-nitropropionic acid model of Huntington's disease (HD). In this study, PN401 increased survival and improved motor function on the rotarod in both R6/2 and N171-82Q polyglutamine repeat mouse models of HD. PN401 significantly decreased neurodegeneration in both the piriform cortex and striatum although PN401 decreased huntingtin protein aggregates only in the striatum. Cortical and striatal brain-derived neurotrophic factor (BDNF) protein levels were reduced in the +/- compared to the -/- N171-82Q mice and PN401 treatment significantly increased cortical BDNF in both +/- and -/- mice, but PN401 did not affect striatal BDNF. These results suggest that PN401 may have beneficial effects in the treatment of neurodegenerative diseases such as HD.

The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.

In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.

Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.

Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading components of the extracellular matrix. Recent evidence has implicated MMPs in the pathogenesis of neurodegenerative diseases as Alzheimer's disease and amyotrophic lateral sclerosis. In this study, we investigated the involvement of MMP-9 (gelatinase B) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease using zymography, immunohistochemistry, and Western blot analysis. The activity of MMP-9 was upregulated at 3 h after MPTP injection in the striatum and after 24 h in the substantia nigra. Although MMP-9 expression decreased in the striatum by 72 h, it remained elevated in the substantia nigra compared to controls up to 7 d after MPTP administration. Immunohistochemistry showed that neurons and microglia are the source of MMP-9 expression after MPTP administration to mice. Treatment with a hydroxamate-based MMP inhibitor, Ro 28-2653 significantly reduced dopamine depletion and loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. MMP-9 expression as measured via zymography in the substantia nigra was reduced by the MMP inhibitor. These results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.

Minocycline enhances MPTP toxicity to dopaminergic neurons.

Minocycline has been shown previously to have beneficial effects against ischemia in rats as well as neuroprotective properties against excitotoxic damage in vitro, nigral cell loss via 6-hydroxydopamine, and to prolong the life-span of transgenic mouse models of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). We investigated whether minocycline would protect against toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively destroys nigrostriatal dopaminergic (DA) neurons and produces a clinical state similar to Parkinson's disease (PD) in rodents and primates. We found that although minocycline inhibited microglial activation, it significantly exacerbated MPTP-induced damage to DA neurons. We present evidence suggesting that this effect may be due to inhibition of DA and 1-methyl-4-phenylpridium (MPP+) uptake into striatal vesicles.