1,721,221 research outputs found
MPTP Neurotoxicity: Actions, Mechanisms, and Animal Modeling of Parkinson’s Disease
No full textThe study of neurotoxicity induced by MPTP led to drastically change the
perspective on Parkinson’s disease. In fact, the selective neurotoxicity induced
by MPTP rejuvenated PD research and generated a number of studies aimed at
elucidating the mechanisms of action of MPTP. Remarkably, these molecular
mechanisms turned out to be critical also for the survival of DA neurons in
idiopathic PD. In this chapter, the main concepts developed over the last three
decades to understand key molecular steps which are pivotal in MPTP toxicity are
reported. This is the case of the role played by DAT and VMAT-2 in conditioning
the sensitivity to MPTP neurotoxicity. Similarly, the mitochondria as targets of
MPTP toxicity appear similarly affected by selective mutation of genes leading to
PD. Again, the fate of mitochondria and the ability to clear these organelles when
being dysfunctional are key in the modulation of MPTP toxicity. This also applies
for misfolded proteins such as alpha-synuclein. Again, multiple brain areas as
well as peripheral sites are increasingly recognized to be affected both during
MPTP toxicity and sporadic PD patients. Nowadays, it seems that MPTP per se
did not lead to the discovery of the environmental compound which causes PD;
nonetheless, the study of MPTP did disclose several molecular and cellular
pathways which are critical in the genesis of PD. This latter point fairly corresponds
to what enthusiastically is expected from MPTP when it was identified as
a causal agent of what it remains, a toxic form of environmental parkinsonism
mTOR-related cell-clearing systems in epileptic seizures, an update
Full text linkRecent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activit
Apomorphine as a neuroprotective drug: a study in MPTP-treated mice and potential relevance to ischemia
No full textNo available abstrac
MPTP-INDUCED PARKINSONISM REVEALS THE NATURE OF CATECHOLAMINE-CONTAINING NEURONS IN THE MOUSE ENTERIC NERVOUS SYSTEM
No full textParkinson’s disease (PD) is a degenerative condition which affects dopaminergic neurons of the substantia nigra, leading to movement impairment, although visceral activities, especially at gastrointestinal level, are also affected. In this study, an attempt was made to reproduce these digestive dysfunctions by using the parkinsonism-inducing neurotoxin 1-methyl, 4-phenyl, 1,2,3,6,-tetrahydropyridine (MPTP) in 9-week old C57BL mice. One week after treatment with MPTP (i.p. 20 mg/kg x3, 2 h apart) morphological and biochemical changes on the nervous network of the gut were examined: tyrosine hydroxylase (TH), dopamine (DA) transporter (DAT) and norepinephrine (NE) transporter (NET) by immunostaining; catecholamine levels by HPLC-ED. In control mice, TH immunopositivity was well evident in both myenteric and submucous plexuses, as continuous markedly stained rings. From the submucous plexus, nervous fibres and neurons extended to the mucosa up to the axes of the villi. DAT and NET immunopositivity also appeared as stained rings. In MPTP-treated mice, both TH and DAT, but not NET, immunopositive neurons decreased in both plexuses and the continuous ring-like staining was no longer evident. Consistently, while NE levels were unchanged, there was a severe DA depletion. These morphological and biochemical changes were accompanied by a functional impairment which was reminiscent of constipation occurring in PD. These data provide a reliable model to investigate the altered gastrointestinal function in PD, and offer the basis to interpret the digestive dysfunction in PD as a consequence of a selective dopaminergic loss, thus confirming that DA neurons would be the sole catecholamine cells within intrinsic circuitries affecting gut motility and secretions
MTOR modulates intercellular signals for enlargement and infiltration in glioblastoma multiforme
Full text linkRecently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications
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