MRS3997, a dual adenosine A/A receptor agonist, reduces brain ischemic damage and alleviates neuroinflammation in rats.

The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A, A, A and A receptors (ARs, ARs, ARs and ARs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of ARs, as well as ARs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both ARs and ARs, would afford higher neuroprotection in post-ischemic damage.

Adenosine A receptors differently modulate oligodendrogliogenesis and myelination depending on their cellular localization.

Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the brain; this process fails during demyelinating pathologies. Adenosine is emerging as an important player in oligodendrogliogenesis, by activating its metabotropic receptors (AR, AR, AR, and AR). We previously demonstrated that the Gs-coupled AR reduced differentiation of primary OPC cultures by inhibiting delayed rectifier (I) as well as transient (I) outward K currents.

Adenosine A receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult.

During brain ischemia, excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage. Indeed, anoxic depolarization, consisting of massive neuronal depolarization due to the loss of membrane ion gradients, occurs in vivo or in vitro during an energy failure. The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors, namely: A, A, A, and A.

Pharmacological Characterization of P626, a Novel Dual Adenosine A/A Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus.

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (AAR, AAR, AAR, AAR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of AAR or AAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus.

Covalently Binding Adenosine A Receptor Agonist ICBM Irreversibly Reduces Voltage-Gated Ca Currents in Dorsal Root Ganglion Neurons.

Interest has been focused in recent years on the analgesic effects exerted by adenosine and its receptors, A, A, A, and A adenosine receptor (AR) subtypes, in different in vivo models of chronic pain. In particular, it was demonstrated that selective AAR agonists reduced pro-nociceptive N-type Ca channels in dorsal root ganglion (DRG) neurons isolated from rats and, by this mechanism, inhibit post inflammatory visceral hypersensitivity. In the present study, we investigate the effect of a previously reported irreversibly binding AAR agonist, ICBM, on Ca currents (I) in rat DRG neurons.

Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke.

Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantification of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke.

Selective block of adenosine A receptors prevents ischaemic-like effects induced by oxygen and glucose deprivation in rat medium spiny neurons.

Background And Purpose: Ischaemia is known to cause massive neuronal depolarization, termed anoxic depolarization (AD), due to energy failure and loss of membrane ion gradients. The neuromodulator adenosine accumulates extracellularly during ischaemia and activates four metabotropic receptors: A , A , A and A . Striatal medium spiny neurons (MSNs) express high levels of A receptors and are particularly vulnerable to ischaemic insults.

Therapeutic Potential of Highly Selective A Adenosine Receptor Ligands in the Central and Peripheral Nervous System.

Ligands of the G protein-coupled adenosine A receptor (AR) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g.

Targeting the RNA-Binding Protein HuR as Potential Thera-Peutic Approach for Neurological Disorders: Focus on Amyo-Trophic Lateral Sclerosis (ALS), Spinal Muscle Atrophy (SMA) and Multiple Sclerosis.

The importance of precise co- and post-transcriptional processing of RNA in the regulation of gene expression has become increasingly clear. RNA-binding proteins (RBPs) are a class of proteins that bind single- or double-chain RNA, with different affinities and selectivity, thus regulating the various functions of RNA and the fate of the cells themselves. ELAV (embryonic lethal/abnormal visual system)/Hu proteins represent an important family of RBPs and play a key role in the fate of newly transcribed mRNA.

Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A Receptor Subtype.

Agonists of the G protein-coupled A adenosine receptor (AAR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, AAR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain.

Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation.

A Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis.

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs).

Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents.

Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification.

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study.

Focal repetitive transcranial magnetic stimulation (rTMS) has been applied to improve cognition in Alzheimer's disease (AD) with conflicting results. We applied rTMS in AD in a pilot placebo-controlled study using the H2-coil. H-coils are suitable for targeting wider neuronal structures compared with standard focal coils, in particular the H2-coil stimulates simultaneously the frontal-parietal-temporal lobes bilaterally.

Adenosine A3 agonists reverse neuropathic pain via T cell-mediated production of IL-10.

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown.

Dexpramipexole Enhances K Currents and Inhibits Cell Excitability in the Rat Hippocampus In Vitro.

Dexpramipexole (DEX) has been described as the first-in-class F1Fo ATP synthase activator able to boost mitochondrial bioenergetics and provide neuroprotection in experimental models of ischemic brain injury. Although DEX failed in a phase III trial in patients with amyotrophic lateral sclerosis, it showed favorable safety and tolerability profiles. Recently, DEX emerged as a Nav1.

Oligodendrocyte precursor cell maturation: role of adenosine receptors.

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain and their degeneration leads to demyelinating diseases such as multiple sclerosis. Remyelination requires the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes but, in chronic neurodegenerative disorders, remyelination fails due to adverse environment. Therefore, a strategy to prompt oligodendrocyte progenitor cell differentiation towards myelinating oligodendrocytes is required.

Photobiomodulation of Human Fibroblasts and Keratinocytes with Blue Light: Implications in Wound Healing.

In recent years, photobiomodulation (PBM) has been recognized as a physical therapy in wound management. Despite several published research papers, the mechanism underlying photobiomodulation is still not completely understood. The investigation about application of blue light to improve wound healing is a relatively new research area.

A Adenosine Receptors: When Outsiders May Become an Attractive Target to Treat Brain Ischemia or Demyelination.

Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing AR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia.

Oxidative stress mediates thalidomide-induced pain by targeting peripheral TRPA1 and central TRPV4.

Background: The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism.

Experimental Study on Blue Light Interaction with Human Keloid-Derived Fibroblasts.

Keloids are an exuberant response to wound healing, characterized by an exaggerated synthesis of collagen, probably due to the increase of fibroblasts activity and to the reduction of their apoptosis rate: currently no standard treatments or pharmacological therapies are able to prevent keloid recurrence. To reach this goal, in recent years some physical treatments have been proposed, and among them the PhotoBioModulation therapy (PBM). This work analyses the effects of a blue LED light irradiation (410-430 nm, 0.

Multicentre translational Trial of Remote Ischaemic Conditioning in Acute Ischaemic Stroke (TRICS): protocol of multicentre, parallel group, randomised, preclinical trial in female and male rat and mouse from the Italian Stroke Organization (ISO) Basic Science network.

Introduction: Multicentre preclinical randomised controlled trials (pRCT) are emerging as a necessary step to confirm efficacy and improve translation into the clinic. The aim of this project is to perform two multicentre pRCTs (one in rats and one in mice) to investigate the efficacy of remote ischaemic conditioning (RIC) in an experimental model of severe ischaemic stroke.

Methods And Analysis: Seven research laboratories within the Italian Stroke Organization (ISO) Basic Science network will participate in the study.

Acetylcholine modulates K and Na currents in human basal forebrain cholinergic neuroblasts through an autocrine/paracrine mechanism.

The Nucleus Basalis of Meynert (NBM) is the main source of cholinergic neurons in the basal forebrain to be crucially involved in cognitive functions and whose degeneration correlates with cognitive decline in major degenerative pathologies as Alzheimer's and Parkinson's diseases. However, knowledge concerning NBM neurons derived from human brain is very limited to date. We recently characterized a primary culture of proliferating neuroblasts isolated from the human fetal NBM (hfNBM) as immature cholinergic neurons expressing the machinery to synthetize and release acetylcholine.