neuroprotective

Pharmacological exploitation of neurotrophins and their receptors to develop novel therapeutic approaches against neurodegenerative diseases and brain trauma

Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.

Protective microglial signaling in Alzheimer's Disease

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030

Ebselen: a lithium-mimetic without lithium side-effects?

Development of new medications for mental health conditions is a pressing need given the high proportion of people not responding to available treatments. We hope that presenting ebselen to a wider audience will inspire further studies on this promising agent with a benign side-effects profile. Laboratory research, animal research and human studies suggest that ebselen shares many features with the mood stabilising drug lithium, creating a promise of a drug that would have a similar clinical effect but without lithium’s troublesome side-effect profile and toxicity. Both drugs have a common biological target, inositol monophosphatase, whose inhibition is thought key to lithium’s therapeutic effect. Both drugs have neuroprotective action and reduce oxidative stress. In animal studies, ebselen affected neurotransmitters involved in the development of mental health symptoms, and in particular, produced effects of serotonin function very similar to lithium. Both ebselen and lithium share behavioural effects: antidepressant-like effects in rodent models of depression and decrease in behavioural impulsivity, a property associated with lithium's anti-suicidal action. Human neuropsychological studies support an antidepressant profile for ebselen based on its positive impact on emotional processing and reward seeking. Our group currently is exploring ebselen’s effects in patients with mood disorders. A completed ‘add-on’ clinical trial in mania showed ebselen’s superiority over placebo after three weeks of treatment. Our ongoing experimental research explores ebselen’s antidepressant profile in patients with treatment resistant depression. If successful, this will lead to a clinical trial of ebselen as an antidepressant augmentation agent, similar to lithium.

The pathophysiology of prodromal Parkinson’s disease

Studying the pathophysiology of late stage Parkinson’s disease (PD) – after the patients have experienced severe neuronal loss – has helped develop various symptomatic treatments for PD (e.g., deep brain stimulation). However, it has been of limited use in developing neuroprotective disease-modifying therapies (DMTs), because DMTs require interventions at much earlier stages of PD when vulnerable neurons are still intact. Because PD patients exhibit various non-motor prodromal symptoms (ie, symptoms that predate diagnosis), understanding the pathophysiology underlying these symptom could lead to earlier diagnosis and intervention. In my talk, I will present a recently elucidated example of how PD pathologies alter the channel biophysics of intact vagal motoneurons (known to be selectively vulnerable in PD) to drive dysautonomia that is reminiscent of prodromal PD. I will discuss how elucidating the pathophysiology of prodromal symptoms can lead to earlier diagnosis through the development of physiological biomarkers for PD.

Hughlings Jackson Lecture: Making Progress in Progressive MS – the Ultimate Challenge!

On April 22, 2021, Dr. Alan J Thompson of the University College London and the UCL Institute of Neurology, London, UK will deliver the Hughlings Jackson Lecture entitled, “Making Progress in Progressive MS – the Ultimate Challenge!” Established in 1935, the Hughlings Jackson Lecture is The Neuro’s premier scientific lecture. It honors the legacy of British neurologist John Hughlings Jackson (1835-1911) who pioneered the development of neurology as a medical specialty. Talk Abstract : The international focus on progressive MS, driven by the Progressive MS Alliance amongst others, together with recent encouraging results from clinical trials have raised the profile and emphasised the importance of understanding, treating and ultimately preventing progression in MS. Effective treatment for Progressive MS is now regarded as the single most important issue facing the MS community. There are several important challenges to developing new treatments for progressive MS. Fundamental to any development in treatment is a better understanding of the mechanisms of tissue injury underpinning progression which will in turn allow the identification of new targets against which treatments can be directed. There are additional complications in determining when progression actually starts, determining the impact of aging and defining the progressive clinical phenotypes – an area which has become increasingly complex in recent months. Evaluating potential new treatments in progressive MS also poses particular challenges including trial design and the selection of appropriate clinical and imaging outcomes - in particular, identifying an imaging biomarker for phase II trials of progressive MS. Despite these challenges, considerable progress is being made in developing new treatments targeting the innate immune system and exploring neuroprotective strategies. Further advances are being driven by a number of international networks, funded by the Progressive MS Alliance. Overall we are seeing encouraging progress as a result of co-ordinated global collaboration which offers real possibilities for truly effective treatment of progression.

Using human pluripotent stem cells to model obesity in vitro

Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets. ​

Ex vivo gene therapy for epilepsy. Seizure-suppressant and neuroprotective effects of encapsulated GDNF-producing cells

A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the patients. Thus, developing more targeted and effective treatment strategies is highly warranted. Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the brain. We have developed an implantable cell encapsulation system that delivers high and consistent levels of neurotrophic molecules directly to a specific brain region. The potential of this approach has been tested by delivering glial cell line-derived neurotrophic factor (GDNF) to the hippocampus of epileptic rats. In vivo studies demonstrated that these intrahippocampal implants continue to secrete GDNF and produce high hippocampal GDNF tissue levels in a long-lasting manner. Identical implants rapidly and greatly reduced seizure frequency in the pilocarpine model. This effect increased in magnitude over 3 months, ultimately leading to a reduction of spontaneous seizures by more than 90%. Importantly, these effects were accompanied by improvements in cognition and anxiety, and by the normalization of many histological alterations that are associated with chronic epilepsy. In addition, the antiseizure effect persisted even after device removal. Finally, by establishing a unilateral epileptic focus using the intrahippocampal kainate model, we found that delivery of GDNF exclusively within the focus suppressed already established spontaneous recurrent seizures. Together, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner. These findings may form the basis for clinical translation of this approach.

Carnosine negatively modulates pro-oxidant activities of M1 peripheral macrophages and prevents neuroinflammation induced by amyloid-β in microglial cells

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by amyloid-β (1-42) oligomers in mice: implication of transforming growth factor-β1 and oxidative stress

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.

TARGETING ASTROCYTE REACTIVITY TO BETA-AMYLOID PREVENTS OLIGODENDROCYTE MATURATION IMPAIRMENT: NEUROPROTECTIVE POTENTIAL OF CO-ULTRAPEA/LUTEOLIN

FENS Forum 2026

​A STEPWISE 2D-3D SCREENING STRATEGY FOR IDENTIFYING NEUROPROTECTIVE NATURAL COMPOUNDS USING HUMAN NEURONAL MODELS AND MIDBRAIN ORGANOIDS

FENS Forum 2026

MULTIMODAL MRI AND METABOLOMICS REVEAL NEUROPROTECTIVE EFFECTS OF NLRP3 INFLAMMASOME INHIBITION IN A PROGRESSIVE MOUSE MODEL OF MULTIPLE SCLEROSIS

FENS Forum 2026

NEUROPROTECTIVE EFFECTS OF ANTIOXIDANT NITRONES THROUGH MODULATION OF THE NLRP3 INFLAMMASOME IN MICROGLIA

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NEUROPROTECTIVE POTENTIAL OF PAROXYSMAL DEPOLARIZATION SHIFTS

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COMBINATION OF CITICOLINE AND COENZYME Q10 AS ADJUVANT NEUROPROTECTIVE THERAPY FOR GLAUCOMA. AN EXPERIMENTAL STUDY

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BIOCHEMICAL AND MECHANISTIC INSIGHTS INTO THE POTENTIAL ANTI-NEUROINFLAMMATORY AND NEUROPROTECTIVE EFFECT OF DIETARY BEANS BY REGULATING<EM> </EM>NF-ΚB AND PI3K-AKT SIGNALING PATHWAYS

FENS Forum 2026

GLUCOSE SUPPLEMENTATION SUPPORTS THE NEUROPROTECTIVE EFFECT OF SYNAPTIC SILENCING DURING INFLAMMATORY NEURODEGENERATION

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MULTILINE IPSC-BASED DRUG REPURPOSING IDENTIFIES N-ACETYLCYSTEINE AND FELODIPINE AS NEUROPROTECTIVE AGENTS ACROSS DISTINCT GENETIC FORMS OF PARKINSON’S DISEASE

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DUAL MODULATION OF PATHOGENIC AND NEUROPROTECTIVE PATHWAYS IN ALS USING A CHIMERIC SINEUP-BASED RNA CONSTRUCT

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PLGA-FUNCTIONALIZED NANOPARTICLES FOR INTRANASAL DELIVERY OF NEUROPROTECTIVE CUES: AN ALTERNATIVE STRATEGY FOR TARGETED NEURAL SUPPORT

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NEUROPROTECTIVE AND MYOPROTECTIVE EFFECTS OF DIETARY BOLDINE SUPPLEMENTATION ON COGNITIVE AND MOTOR DECLINE DURING AGING

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POTENTIAL NEUROPROTECTIVE EFFECTS OF EPOXY FATTY ACIDS IN RETT SYNDROME

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NEUROPROTECTIVE EFFECTS OF <EM DATA-START="544" DATA-END="562" >MORINGA OLEIFERA</EM> AGAINST MPTP-INDUCED DOPAMINERGIC NEURODEGENERATION IN A MURINE MODEL

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NEUROPROTECTIVE EFFECTS OF DEXAMETHASONE IN ACUTE HIGH-ALTITUDE HYPOXIA-INDUCED NEURODEGENERATION OF RETINAL AND VISUAL CORTICAL NEURONS

FENS Forum 2026

PROTEOMIC INSIGHTS INTO THE NEUROPROTECTIVE EFFECTS OF <EM>EUCALYPTUS CITRIODORA</EM> ESSENTIAL OIL IN A 6-HYDROXYDOPAMINE-INDUCED N2A CELL MODEL

FENS Forum 2026

REPURPOSING RIBOSE, ADENINE AND ALLOPURINOL AS AN ATP-ELEVATING NEUROPROTECTIVE THERAPY FOR ISCHEMIC STROKE

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ANTI-INFLAMMATORY AND NEUROPROTECTIVE EFFECTS OF INFLAMMASOME INHIBITORS FOLLOWING CONTUSION SPINAL CORD INJURY

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INFLUENCE OF SEX AND MOUSE LINEAGE ON THE NEUROPROTECTIVE EFFECTS OF CILASTATIN IN GLAUCOMA

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BLOOD GLUTAMATE SCAVENGING AS A NEUROPROTECTIVE APPROACH IN NEUROTRAUMA

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CB<SUB>1</SUB>R–OX<SUB>2</SUB>R HETEROMER IN ALZHEIMER’S DISEASE: IMPLICATIONS FOR NEURONAL NEUROPROTECTIVE SIGNALING

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METAGENOMIC PROFILING OF ALZHEIMER’S BRAINS REVEALS A SHIFT FROM NEUROPROTECTIVE COMMENSALS TO OPPORTUNISTIC PATHOGENS

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EVALUATION OF THE NEUROPROTECTIVE EFFECT OF AGMATINE IN FEMALE MICE WITH RECURRENT ISCHEMIC STROKE

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NEUROPROTECTIVE AND IMMUNOMODULATORY EFFECTS OF NEAR-INFRARED PHOTOBIOMODULATION IN IN VITRO MODELS OF HYPOXIC–ISCHEMIC ENCEPHALOPATHY

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NEUROPROTECTIVE EFFICACY OF THE PDE INHIBITOR IBUDILAST IN A CHRONIC MPTP MODEL OF PARKINSON’S DISEASE

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NEUROPROTECTIVE AND NEUROREGENERATIVE PROPERTIES OF DIRECT TRPV1 RECEPTOR AGONIST CAPSAICIN ON DORSAL ROOT GANGLIA

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HIPPOCAMPAL OVEREXPRESSION OF THE MRNA POLYADENYLATION REGULATOR CPEB4 REDUCES SEIZURE SEVERITY AND CONFERS NEUROPROTECTIVE EFFECTS IN A MOUSE MODEL OF ACUTE SEIZURES

FENS Forum 2026

NEUROPROTECTIVE EFFECTS OF ZINC SUPPLEMENTATION ON BEHAVIOR, SYNAPTIC INTEGRITY, AND NEUROINFLAMMATION IN PREFRONTAL CORTEX AND HIPPOCAMPUS IN A PRENATAL VALPROIC ACID-INDUCED MODEL OF AUTISM

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PURKINJE CELL COMPLEX SPIKES AND NEUROPROTECTIVE MOLECULAR IDENTITY IN SPINOCEREBELLAR ATAXIA TYPE 13

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CRISPR ACTIVATION AS A NEUROPROTECTIVE STRATEGY FOR SPINOCEREBELLAR ATAXIA TYPE 3

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​<EM>BLOOD CELL–DERIVED SECRETOME AS A NEUROPROTECTIVE STRATEGY IN COMORBIDITY-RELEVANT MODELS OF ISCHEMIC STROKE</EM>

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DIZOCILPINE (MK-801) DERIVATIVES AS NEUROPROTECTIVE NMDA RECEPTOR ANTAGONISTS WITHOUT PSYCHOMIMETIC SIDE EFFECTS

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CHARACTERIZATION OF NEUROPROTECTIVE EFFECTS MEDIATED BY PROLYL ENDOPEPTIDASE-INHIBITORY COMPOUNDS FOR THE TREATMENT OF PARKINSON’S DISEASE

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NEUROPROTECTIVE EFFECTS OF VEGF-B IN A MODEL OF SELECTIVE AND LATE NEURONAL DEATH

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DYNAMIC CHANGES IN THE THALAMIC PROTEOME IN FETAL GROWTH RESTRICTED PIGLETS REVEALS EARLY NEUROPROTECTIVE RESPONSES FOLLOWED BY A DECLINE IN OXIDATIVE PHOSPHORYLATION

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NEUROPROTECTIVE ROLE OF BAVACHIN IN A RAT MIDDLE CEREBRAL ARTERY OCCLUSION STROKE MODEL

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MAGNESIUM SULPHATE EXHIBITS NEUROPROTECTIVE ACTIVITY IN NEONATAL HYPOXIC BRAIN INJURY BY IMPROVING THE SURVIVAL AND DIFFERENTIATION OF PRE-MYELINATING OLIGODENDROCYTES <EM>IN VITRO</EM>

FENS Forum 2026

Application of dehydroepiandrosterone as a neuroprotective agent for the therapy of Alzheimer’s disease in a mouse model

FENS Forum 2024

The more, the better? Neuroprotective effects of different drug- and stem cell-based therapies as novel approaches for neurodegenerative diseases

Targeting oxidative stress and prolyl hydroxylase domain inhibition as neuroprotective strategies against hypoxia in isolated rat hippocampal slices