9 research outputs found
The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research
Neuroprotective role of lactate in a human in vitro model of the ischemic penumbra
In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect stressed yet viable brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. Here, we hypothesized that neuronal activation might maintain or trigger the astrocyte-to-neuron lactate shuttle (ANLS), whereby lactate is released from astrocytes to support the energy requirements of ATP-starved hypoxic neurons, and this leads to the observed neuroprotection. We tested this by using a human cell based in vitro model of the ischemic penumbra and investigating whether lactate might be neuroprotective in this setting. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation. Furthermore, we showed that lactate exogenously administered before hypoxia correlated with neuroprotection in our cellular model. In addition, stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. To conclude, here we presented evidence that lactate transport into neurons contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.</p
The Internalization of Externalities in the Production of Electricity: Willingness to Pay for the Attributes of a Policy for Renewable Energy
Nicotinic acetylcholine receptors and epilepsy
Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy
A New Workflow for Proteomic Analysis of Urinary Exosomes and Assessment in Cystinuria Patients
Cystinuria is a purely renal, rare
genetic disease caused by mutations
in cystine transporter genes and characterized by defective cystine
reabsorption leading to kidney stones. In 14% of cases, patients undergo
nephrectomy, but given the difficulty to predict the evolution of
the disease, the identification of markers of kidney damage would
improve the follow-up of patients with a higher risk. The aim of the
present study is to develop a robust, reproducible, and noninvasive
methodology for proteomic analysis of urinary exosomes using high
resolution mass spectrometry. A clinical pilot study conducted on
eight cystinuria patients versus 10 controls highlighted 165 proteins,
of which 38 were up-regulated, that separate cystinuria patients from
controls and further discriminate between severe and moderate forms
of the disease. These proteins include markers of kidney injury, circulating
proteins, and a neutrophil signature. Analysis of selected proteins
by immunobloting, performed on six additional cystinuria patients,
validated the mass spectrometry data. To our knowledge, this is the
first successful proteomic study in cystinuria unmasking the potential
role of inflammation in this disease. The workflow we have developed
is applicable to investigate urinary exosomes in different renal diseases
and to search for diagnostic/prognostic markers. Data are available
via ProteomeXchange with identifier PXD001430