The mammalian neocortex is established from neural stem and progenitor cells that utilize specific transcriptional and environmental factors to create functional neurons and astrocytes. Here, we examined the mechanism of Sox2 action during neocortical neurogenesis and gliogenesis. We established a robust Sox2 expression in neural stem and progenitor cells within the ventricular zone, which persisted until the cells exited the cell cycle. Overexpression of constitutively active Sox2 in neural progenitors resulted in upregulation of Notch1, recombination signal-sequence binding protein-J (RBP-J) and hairy enhancer of split 5 (Hes5) transcripts and the Sox2 high mobility group (HMG) domain seemed sufficient to confer these effects. While Sox2 overexpression permitted the differentiation of progenitors into astroglia, it inhibited neurogenesis, unless the Notch pathway was blocked. Moreover, neuronal precursors engaged a serine protease(s) to eliminate the overexpressed Sox2 protein and relieve the repression of neurogenesis. Glial precursors and differentiated astrocytes, on the other hand, maintained Sox2 expression until they reached a quiescent state. Sox2 expression was re-activated by signals that triggered astrocytic proliferation (i.e., injury, mitogenic and gliogenic factors). Taken together, Sox2 appears to act upstream of the Notch signaling pathway to maintain the cell proliferative potential and to ensure the generation of sufficient cell numbers and phenotypes in the developing neocortex.
Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B-induced shock, and middle cerebral artery occlusion-induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex.
Collapsin response mediator proteins (CRMPs) are important brain-specific proteins with distinct functions in modulating growth cone collapse and axonal guidance during brain development. Our previous studies have shown that calpain cleaves CRMP3 in the adult mouse brain during cerebral ischemia [S.T. Hou et al. (2006) J. Neurosci., 26, 2241-2249]. Here, the expression of all CRMP family members (1-5) was examined in mouse brains that were subjected to middle cerebral artery occlusion. Among the five CRMPs, the expressions of CRMP1, CRMP3 and CRMP5 were the most abundant in the cerebral cortex and all CRMPs were targeted for cleavage by ischemia-activated calpain. Sub-cellular fractionation analysis showed that cleavage of CRMPs by calpain occurred not only in the cytoplasm but also in the synaptosomes isolated from ischemic brains. Moreover, synaptosomal CRMPs appeared to be at least one-fold more sensitive to cleavage compared with those isolated from the cytosolic fraction in an in-vitro experiment, suggesting that synaptosomal CRMPs are critical targets during cerebral ischemia-induced neuronal injury. Finally, the expression of all CRMPs was colocalized with TUNEL-positive neurons in the ischemic mouse brain, which further supports the notion that CRMPs may play an important role in neuronal death following cerebral ischemia. Collectively, these studies demonstrated that CRMPs are targets of calpains during cerebral ischemia and they also highlighted an important potential role that CRMPs may play in modulating ischemic neuronal death.
E2F1+/- mice subjected to 2 h middle cerebral artery occlusion developed an infarct of 77.0 +/- 3.2 mm3 (mean +/- s.e.m., n = 15) in the ischemic hemisphere after 24 h reperfusion. A significantly smaller infarct of 58.8 +/- 4.8 mm3 (n = 15; p < 0.01) was found in E2F1-/- animals. Both deficient and normal mice had similar cerebral angioarchitecture and intra-ischemic decreases in regional blood flow. Similar areas of hypoxia in both groups of ischemic animals were demonstrated directly by immunohistochemical detection of nitroimidazole adducts. It was concluded that all animals received the same ischemic insult, yet the subsequent damage was different in the mutant mice. This is the first indication that the E2F1 gene plays a role in ischemic death of post-mitotic neurons.
Although the support for the use of antioxidants, such as coenzyme Q 10 (CoQ 10 ), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ 10 is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ 10 (Ubisol-Q 10 ) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q 10 was delivered in drinking water. Prophylactic application of Ubisol-Q 10 , started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q 10 group by day 28). Therapeutic application of Ubisol-Q 10 , given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q 10 concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ 10 /kg body weight/day, showing clearly that high doses of CoQ 10 were not required to deliver these effects. Furthermore, the Ubisol-Q 10 treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q 10 was capable of halting the neurodegeneration already in progress;
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