Involvement of calpains in adult neurogenesis: implications for stroke

Calpains are ubiquitous proteases involved in cell proliferation, adhesion and motility. In the brain, calpains have been associated with neuronal damage in both acute and neurodegenerative disorders, but their physiological function in the nervous system remains elusive. During brain ischemia, there is a large increase in the levels of intracellular calcium, leading to the activation of calpains. Inhibition of these proteases has been shown to reduce neuronal death in a variety of stroke models. On the other hand, after stroke, neural stem cells (NSC) increase their proliferation and newly formed neuroblasts migrate towards the site of injury. However, the process of forming new neurons after injury is not efficient and finding ways to improve it may help with recovery after lesion. Understanding the role of calpains in the process of neurogenesis may therefore open a new window for the treatment of stroke. We investigated the involvement of calpains in NSC proliferation and neuroblast migration in two highly neurogenic regions in the mouse brain, the dentate gyrus (DG) and the subventricular zone (SVZ). We used mice that lack calpastatin, the endogenous calpain inhibitor, and calpains were also modulated directly, using calpeptin, a pharmacological calpain inhibitor. Calpastatin deletion impaired both NSC proliferation and neuroblast migration. Calpain inhibition increased NSC proliferation, migration speed and migration distance in cells from the SVZ. Overall, our work suggests that calpains are important for neurogenesis and encourages further research on their neurogenic role. Prospective therapies targeting calpain activity may improve the formation of new neurons following stroke, in addition to affording neuroprotection.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PTDC/SAU-NMC/112183/2009, PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014]; NIH [GM 23244]; FCT [SFRH/BPD/78901/2011, SFRH/BD/38127/2007, SFRH/BD/78050/2011]info:eu-repo/semantics/publishedVersio

Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

© 2017.Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF + BM-MSC or G-CSF + BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. Conclusion: While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time

New Antidepressant Medication: Benefits Versus Adverse Effects

Depression [major depressive disorder (MDD)] is a mood disturbance of multifactorial origin, associated with high rates of morbidity and mortality, lack of work productivity, adverse health behaviors, and increased healthcare expenses. MDD is a leading cause of suicide, and it affects the prognosis of chronic conditions (heart diseases, diabetes, and cancer, among others). Current pharmacological treatment for MDD covers different classes of drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants. The aim of this chapter is to review the literature, highlight the side effects of newer antidepressants, and especially point out the most important aspects of the latest agents approved for the treatment of MDD in adults: desvenlafaxine, levomilnacipran, vilazodone, and vortioxetine. Desvenlafaxine is a SNRI and the primary active metabolite of venlafaxine; also a SNRI, levomilnacipran is an enantiomer of the racemate milnacipran. Vilazodone and vortioxetine are multimodal antidepressants, which combine SSRI activity with additional receptor activity. Although they have proven efficacy in treating MDD and are being investigated for other possible indications, further detailed clinical trials are needed to establish their pharmaco-toxicological profile, following prolonged administration in patients who may suffer from various comorbidities

Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats

© Copyright © 2020 Balseanu, Grigore, Pinosanu, Slevin, Hermann, Glavan and Popa-Wagner. The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of the Alzheimer’s disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus

Repeated PTZ Treatment at 25-Day Intervals Leads to a Highly Efficient Accumulation of Doublecortin in the Dorsal Hippocampus of Rats

BACKGROUND: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined, and identifying an in vivo correlate of neurogenesis has become an important goal. By studying pentylenetetrazole-induced brain stimulation in a rat model of kindling we accidentally discovered that 25±1 days periodic stimulation of Sprague-Dawley rats led to a highly efficient increase in seizure susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: By EEG, RT-PCR, western blotting and immunohistochemistry, we show that repeated convulsive seizures with a periodicity of 25±1 days led to an enrichment of newly generated neurons, that were BrdU-positive in the dentate gyrus at day 25±1 post-seizure. At the same time, there was a massive increase in the number of neurons expressing the migratory marker, doublecortin, at the boundary between the granule cell layer and the polymorphic layer in the dorsal hippocampus. Some of these migrating neurons were also positive for NeuN, a marker for adult neurons. CONCLUSION/SIGNIFICANCE: Our results suggest that the increased susceptibility to seizure at day 25±1 post-treatment is coincident with a critical time required for newborn neurons to differentiate and integrate into the existing hippocampal network, and outlines the importance of the dorsal hippocampus for seizure-related neurogenesis. This model can be used as an in vivo correlate of neurogenesis to study basic questions related to neurogenesis and to the neurogenic mechanisms that contribute to the development of epilepsy

A Reliable and Manufacturable Method to Induce a Stress of GPa on a P-Channel MOSFET in High Volume Manufacturing

The article of record as published may be found at http://dx.doi.org/10.1109/LED.2005.862277This letter discusses a reliable and manufacturable integration technique to induce greater than 1 GPa of stress into a p-channel MOSFET, which will be required to increase the drive current beyond 1 mA/ m at the sub-90-nm process generation. Uniaxial compressive stress is introduced into the p-channel by both a selective deposition of SiGe in the source/drain and an engineered 2.5-GPa compressively stressed nitride. The highest to date compressively stressed SiN film is obtained by heavy ion bombardment during the deposition of the film.Thin Films Group at Applied Material

Post Deposition Ultraviolet Treatment of Silicon Nitride Dielectric: Modeling and Experiment

AbstractSimulation and FTIR analysis of the UV treatment impact on bond strengths of PECVD deposited silicon nitride films</jats:p

Stress Modulation of PECVD Silicon Nitride

Abstract not Available.</jats:p