•Clinical trials with neuroprotective drugs have failed in stroke.•Glutamate and GABA crucially contribute to ischemic pathobiology.•Grabbing glutamate or targeting extrasynaptic NMDA receptors are ...promising strategies.•A fine modulation of glutamate/GABA balance underlies ischemic tolerance.
The search for neuroprotection in acute ischemic stroke has been dramatically disappointing, with virtually all clinical trials failed for excessive toxicity or lack of efficacy of the tested drug; whereby, current treatments are exclusively based on reperfusion. Given the crucial role of amino acid neurotransmission in ischemic pathobiology, numerous failed strategies were aimed at blocking ionotropic glutamate receptor-mediated excitotoxicity or potentiating GABA-mediated inhibition. Recent work has revived the interest of pharmacologists toward glutamate and GABA receptors, due to a better understanding of subtype-specific toxicity and their involvement in ischemic tolerance. Thus, blocking receptor stimulation through glutamate grabbing, inhibiting downstream transduction pathways or selectively antagonizing detrimental NMDA receptor subpopulations represent promising strategies to rescue ischemic brain injury with limited side effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The global impact of dementia is an increasing area of concern and, according to the Alzheimer’s Disease International (ADI) World Alzheimer Report 2021, up to 90% of dementia patients in low- and ...middle-income countries are not diagnosed ...
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In both excitable and non-excitable cells, calcium (Ca
) signals are maintained by a highly integrated process involving store-operated Ca
entry (SOCE), namely the opening of plasma membrane (PM) Ca
...channels following the release of Ca
from intracellular stores. Upon depletion of Ca
store, the stromal interaction molecule (STIM) senses Ca
level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca
refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca
signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca
homeostasis or mediate Ca
overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson's disease (PD) models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer's disease (AD) pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington's disease (HD) transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up-regulation of SOCE may be beneficial during AD. These intriguing findings highlight the importance of further mechanistic studies to dissect the molecular pathways, and their corresponding targets, involved in synaptic dysfunction and neuronal loss during aging and neurodegenerative diseases.
Background
the interest of clinical reaseach in polymorphisms and epigenetics in migraine has been growing over the years. Due to the new era of preventative migraine treatment opened by monoclonal ...antibodies (mAbs) targeting the signaling of the calcitonin-gene related peptide (CGRP), the present systematic review aims at identifying genetic variants occurring along the CGRP pathway and at verifying whether these can affect the clinical features and the course of disease and the responsiveness of patients to therapy.
Methods
the literature search has been conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science, the Human Genome Epidemiology (HuGE) Published Literature database (Public Health Genomics Knowledge Base) and Clinicaltrials.gov from database inception until April 1, 2021. The process of identification and selection of the studies included in the analysis has followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses and the guidance from the Human Genome Epidemiology Network for reporting gene-disease associations.
Results
the search has retrieved 800 results, among which only 7 studies have met the eligibility criteria for inclusion in the analysis. The latter are case-control studies of genetic association and an exploratory analysis and two polymorphisms have been detected as the most recurring: the rs3781719 (T > C) of the CALC A gene encoding CGRP and the rs7590387 of the gene encoding the receptor activity-modifying protein (RAMP) 1 (C > G). Only one study assessing the methylation pattern with regard to CGRP pathway has been found from the search. No genetic association studies investigating the possible effect of genetic variants affecting CGRP signaling on the responsiveness to the most recent pharmacological approaches, i.e. anti-CGRP(R) mAbs, gepants and ditans, have been published. According to the Human Genome Epidemiology (HuGE) systematic reviews and meta-analyses risk-of-bias score for genetic association studies, the heterogeneity between and across studies and the small sample size do not allow to draw conclusions and prompt future studies.
Conclusions
adequately powered, good quality genetic association studies are needed to understand the impact of genetic variants affecting the pathway of CGRP on migraine susceptibility and clinical manifestation and to predict the response to therapy in terms of efficacy and safety.
Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery ...and repair. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells, facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells may accumulate in the capillaries, further impairing cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, may release pro-inflammatory mediators, such as cytokines, chemokines and oxygen/nitrogen free radicals that contribute to the evolution of tissue damage. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1β. The present work reviewed the role of neuroinflammatory mediators in the pathophysiology of ischemic brain damage and their potential exploitation as drug targets for the treatment of cerebral ischemia.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4–48 h. In ...episodic migraine, attacks occur in less than 15 days per month and in chronic migraine, in more than 15 monthly days. Whilst successful translation of pharmacological discoveries into efficacious therapeutics has been achieved in the preventative therapy of chronic migraine, treatment of acute migraine suffers the lack of effective advancements. An effective treatment affords complete freedom from pain two hours after therapy and provides the absence of the most bothersome symptom (MBS) associated with migraine after 2 h. However, available anti-migraine abortive treatments for acute attacks do not represent an effective and safe treatment for all the populations treated. In particular, the most used specific treatment is represented by triptans that offer 2-h sustained freedom from pain achieved in 18–50% of patients but they are contraindicated in coronary artery disease, stroke and peripheral vascular disease due to the vasoconstriction at the basis of their pharmacologic action. The most novel therapies, i.e., gepants and ditans, are without sufficient post-marketing data for secure use. Here, an attempt is proposed to analyse the rational basis and evidence in favour of investigating the efficacy and safety in acute migraine attacks of eptinezumab, i.e., monoclonal antibody (mAb) directed towards calcitonin gene-related peptide (CGRP) unique for intravenous infusion administration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Open Angle Glaucoma (POAG) is the leading causes of irreversible blindness
worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma; however,
a subset ...of patients experiences a progression of the disease even in presence of normal intraocular
pressure values. This implies that risk factors other than intraocular pressure are involved in the
pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases
such as Alzheimer Disease has been suggested. In this regard, we recently described a high prevalence
of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3, in a group of patients with
Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure
or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of
dementia with progressive deterioration of memory and cognition. Complaints related to vision are
common among Alzheimer Disease patients.
Methods: In this paper researches related to glaucoma and Alzheimer disease are reviewed.
Results: Diseases characteristics, i.e. common features, risk factors and pathophysiological mechanisms
gathered in the recent literature do suggest that Alzheimer Disease and glaucoma can be considered
both age-related neurodegenerative diseases that may co-exist in the elderly.
Conclusion: In conclusion, preclinical and clinical evidence gathered so far support the notion that
glaucoma is a widespread neurodegenerative condition whose common pathogenetic mechanisms with
other diseases, i.e. Alzheimer Disease, should be further investigated as they may shed new light on
these diseases improving both diagnosis and treatments.
Pain is underdiagnosed and often not adequately treated, contributing to behavioral and psychological symptoms of dementia (BPSD). BPSD are treated with atypical antipsychotics that are associated ...with severe cerebrocardiovascular effects. Interestingly, treatment of pain may reduce agitation. Research is focusing on nonpharmacological treatment, such as aromatherapy, for pain and BPSD in dementia. This clinical study will assess the effect on agitation in severely demented elderly of BEO loaded in a nanotechnological odorless cream indistinguishable from placebo. This is a protocol for a randomized, double‐blind, placebo‐controlled trial (NCT04321889). A total of 134 patients aged ≥65 years with severe dementia (mini‐mental state examination <12) will be recruited and randomly allocated 1:1 to either BEO or placebo group. After baseline screening, BEO (80 mg) cream or placebo cream will be trans‐dermally applied on both arms twice a day for 4 weeks with a 4‐week follow‐up period. The effect on agitation will be the primary endpoint. Any adverse events will be reported. A double‐blind, clinical trial evaluating efficacy and safety of an essential oil endowed with strong analgesic properties has never been carried out before. This study could form the basis for a safer and more effective treatment of BPSD in severe dementia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle ...cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood–brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24–48h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.
•Azithromycin dose-dependently reduces brain damage caused by MCAo in mice.•Azithromycin reduces brain infiltration of neutrophils and inflammatory macrophages.•Neuroprotection is associated with elevation of brain and peritoneal M2 macrophages.•Inhibition of arginase activity counteracted azithromycin-induced neuroprotection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abnormal neuronal and synaptic plasticity occurs in Alzheimer's disease (AD) and depression. The latter, particularly late-life, has been recognized as fundamental in the identification of at-risk ...prodromal stages of AD. The lack of disease-modifying drugs and the off-label use of antipsychotics and antidepressants for neuropsychiatric symptoms (NPSs) have caused a season of therapeutic inappropriateness. To date, the wealth of clinical trials investigating drugs, diverse for structure and mechanism of action, has failed to provide a cure for all the spectrums of NPSs. Psychedelics in microdosing afford promotion of neurogenesis and synaptic plasticity and, recently, have been considered a revolution for the management of depression endowed with faster action and an improved side effect profile than antidepressants. In the current scenario, therefore, the rapid-acting antidepressant esketamine could represent the first-in-class for treatment of NPSs, and this deserves to be demonstrated with an open-label clinical trial.
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•Neuropsychiatric symptoms (e.g. depression) may precede Alzheimer's disease diagnosis.•Off-label antidepressants are often used with limited efficacy and safety.•Rapid-acting antidepressants show robust neurotrophic and anti-inflammatory properties.•A case exists for rapid-acting antidepressants to be trialed in open-label studies for safety and efficacy assessment in Alzheimer's disease neuropsychiatric symptoms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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