Life Sciences » Latest Publications (tag [Neuroscience])

Brainstem GLP-1 neurons modulate physiological satiation and drive sustained weight loss in obese mice

Mon, 30 Mar 2026 07:22:40 GMT

Wanqing Jiang, Cecilia Skoug, Ian Rodrigues, Ernesto Ciabatti, Fiona M. Gribble, Frank Reimann, Daniel I. Brierley, Marie K. Holt, Stefan Trapp

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, known as preproglucagon (PPG) neurons, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if chronic stimulation of PPG neurons is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that PPG neurons in the NTS and intermediate reticular nucleus (IRT) determine meal size, and that their total number is inversely correlated with bodyweight gain. We report that PPG^NTS and PPG^IRT neurons receive distinct monosynaptic inputs, but have convergent efferent projection targets throughout the brain, and that combined ablation of both populations delays the onset of physiological satiation to a degree sufficient to promote weight gain under ad libitum chow fed conditions. Crucially, chronic daily chemogenetic activation of PPG^NTS+IRT neurons drives robust and sustained hypophagia and weight loss in obese mice without notable adverse effects, demonstrating their value as targets for obesity pharmacotherapy.

Molecular Metabolism, May 2026

4-Aryl-2-aminoimidazole analogues of bromoageliferin with antimicrobial activity against Acinetobacter baumannii show in vitro inhibition of translocase MraY on the peptidoglycan biosynthesis pathway

Tue, 24 Mar 2026 09:40:32 GMT

Roisin Murphy, Julia A. Fairbairn, Becca W.A. Baileeves, Phillip J. Stansfeld, Timothy D.H. Bugg

A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage ϕX174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF₃) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19606 (MIC 8 μg/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 μg/mL). The analogues showed 33–47% inhibition of particulate E. coli MraY at 200 μM concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC₅₀ 210 μM). Docking against the structure of E. coli MraY revealed a possible binding site in the “elbow” of bent helix 9, close to Phe-288. This work identifies the MraY-protein E interaction site as a possible target for the antimicrobial activity of bromoageliferin, and establishes a new skeleton for design of non-nucleoside MraY inhibitors.

Bioorganic & Medicinal Chemistry Letters, July 2026

Cytoprotection Concepts for Ischemic Stroke in the Recanalization Era

Fri, 20 Mar 2026 09:56:17 GMT

Boltze J., Fisher M

Recanalization therapies for ischemic stroke, in particular endovascular thrombectomy, have revolutionized acute stroke management. Cytoprotective approaches were unsuccessfully tested in the pre-recanalization era but have seen a renaissance in translational research and early clinical trials as a potential intervention to augment the impact of recanalization therapies. The new clinical trial approaches in which cytoprotective therapies are now being applied require refinement of cytoprotective application strategies. This has a profound impact on both preclinical translational and clinical research. This review summarizes current cytoprotection concepts and explains their rationale based on ischemic stroke pathophysiology and provides an overview of cytoprotection approaches currently under clinical assessment. Preclinical assessment of novel cytoprotective paradigms will require advanced in vivo testing in models resembling human stroke patients as much as possible. The review therefore also describes ways to improve preclinical and translational research with respect to comorbidities and other aspects impacting stroke pathophysiology. Moreover, the role of modern brain imaging approaches is discussed including their use as potential biomarkers or patient selection tools. The review further provides detailed considerations of novel clinical trial design features for cytoprotection trials in the context of recanalization therapies and provides an outlook on potential future research approaches.

Advanced Science, February 2026

Consensus Review of Perioperative Immune Modulation for Endovascular Thrombectomy Following Ischemic Stroke

Thu, 05 Mar 2026 09:21:08 GMT

Ling Cai, Yan Li, Chong Wang, Tim Magnus, Chengye Yao, Xiaoming Hu, Ann M. Stowe, Anna Rosell, Sunghee Cho, Stuart M. Allan, Jieqing Wan, Yulong Ma, Yang Liu, Daniel I. Sessler, Johannes Boltze, Tianlong Wang, Weifeng Yu, Yueman Zhang, Peiying Li,

Ischemic stroke is a major global health burden, leading to considerable mortality and long-term disability. Endovascular thrombectomy and mechanical recanalization have revolutionized acute stroke care. Nonetheless, many patients experience poor long-term neurological outcomes, which are often attributed to the no-reflow phenomenon and activation of inflammatory cascades. The perioperative period of endovascular thrombectomy, managed under either general anesthesia or conscious sedation, represents a critical window where anesthetic strategies may influence recovery through hemodynamic control and possibly immune modulation. This consensus review was generated by an international multidisciplinary expert group and synthesizes preclinical and clinical evidence to evaluate the promise of various immunomodulatory strategies for improving functional outcomes in patients with ischemic stroke following endovascular thrombectomy. Our goal is to provide a foundational reference for future research and development of novel perioperative immune therapies for patients with endovascular thrombectomy.

Stroke, February 2026

Systematic review and meta-analysis of cognitive assessments used to detect deficits in the bilateral carotid artery stenosis model for vascular cognitive impairment

Fri, 20 Feb 2026 10:26:00 GMT

Matthew J Padgett , Nela Fucelova , Johannes Boltze, Timothy J England , Tuuli Hietamies , Karen Horsburgh , Terence J Quinn , Emily S Sena , Lorraine M Work, Marietta Zille, Rebecca C Trueman, Tracy D Farr

Hypoperfusion via bilateral carotid artery stenosis is the most common mouse model of vascular cognitive impairment, but the literature varies surrounding which behavioural tests are most appropriate to detect cognitive deficits in this model. We aimed to address this via a systematic review and meta-analysis. We also aimed to provide a recommendation that also considers how the tests cover the different cognitive domains. We identified 1714 publications and extracted data from 56. Interestingly, only six cognitive behavioural tests were employed across the literature with the most common being the Morris water and radial arm mazes, followed by the Y maze, novel object recognition, open field, and the Barnes maze. While all examined tests were able to detect cognitive impairments in hypoperfused mice, there was a high degree of heterogeneity across the publications, highlighting that not all research groups consistently observed cognitive deficits in the model. There was also evidence of publication bias, and occasionally some publications with extremely high effect sizes were influential. We recommend all tests, but ideally experiments should be complemented with additional approaches that examine a greater range of cognitive functions.

Journal of Cerebral Blood Flow & Metabolism, January 2026

Inflammation modifies breathing phenotype in mice with epilepsy

Wed, 11 Feb 2026 08:51:00 GMT

Amol Mohan Bhandare, Adwoa Boaten, Dylan Dunkwu, Jade Hill, Biborka Balazs, Nicholas Dale

Impaired CO₂ responsiveness in epilepsy can result in hypoventilation and hypercapnia and these respiratory disturbances are key contributors to Sudden Unexpected Death in Epilepsy (SUDEP). While mild to moderate inflammation is known to modulate respiratory function, its specific role in regulating respiratory responses in the context of epilepsy remains unclear. We studied the effects of lipopolysaccharide (LPS)-induced inflammation and microglial inhibition via minocycline during the acute and chronic phases of epilepsy on hypercapnic ventilatory responses (HCVR) in the intrahippocampal kainic acid model of temporal lobe epilepsy in male C57BL/6 mice. LPS treatment during acute seizures and minocycline during spontaneous seizures in the chronic phase of epilepsy restored the impaired HCVR in mice. Notably, LPS treatment during acute seizures also reduced the frequency of spontaneous seizures. In contrast, minocycline given during acute seizures and LPS administered during chronic epilepsy further exacerbated HCVR impairment. Immunohistochemical analysis of chemosensitive retrotrapezoid nucleus (RTN) revealed varied effects of different treatments in epileptic mice on microglia density, morphology and their expression of triggering receptor expressed on myeloid cells 2 (TREM2), P2Y12 receptor, and astrocytic adenosine 2A receptor (A2AR). Overall, the inflammation during epileptogenic or acute phase preserves HCVR and reduces spontaneous seizure frequency in chronic epilepsy, whereas in chronic phase it worsens HCVR. Although not yet fully validated, changes in microglial and astrocytic receptor expression could contribute to this HCVR impairment and may represent a mechanistic target for preserving HCVR in epilepsy; a dysfunction that could potentially lead to SUDEP.

Journal of Neuroinflammation, January 2026

Neuroimmune Regulation by TRPM2 Channels

Wed, 04 Feb 2026 09:00:15 GMT

Xuming Zhang, Mitali Malhotra

Mutual interaction between the nervous and immune systems underpins many pathophysiological processes. Transient Receptor Potential Melastatin 2 (TRPM2) channels are abundantly expressed in both systems, acting as a critical interface of neuroimmune interaction. TRPM2 channels in immune cells participate in innate immunity and immune inflammation by acting as an oxidative stress and metabolic sensor. TRPM2 in neurons functions not only as an oxidative sensor but also a temperature sensor and a pain transducer critical to neuronal death, temperature sensing, thermoregulation, and chronic pain. Cooperation between immune and neuronal TRPM2 influences the outcome of neuroimmune interaction and many diseases such as infection, inflammation, ischemic stroke, pain, and neurodegenerative diseases. Improved understanding of neuronal and immune TRPM2 interaction is essential for therapeutic interventions for the treatment of diseases mediated by TRPM2 channels.

Cells, 2026

A holistic view on disease-modifying aspects, comorbidities, and contemporary neuroprotective approaches

Tue, 03 Feb 2026 10:00:06 GMT

Piotr Walczak, Shen Li, Xunming Ji, Johannes Boltze

Most conditions of the central nervous system (CNS) and the peripheral nervous system are not stand-alone disorders but are modulated and influenced by other pathobiological processes. For instance, the impact of frequent comorbidities such as hypertension or dyslipidemia as factors contributing to and aggravating CNS diseases has been much better understood in recent years. Another prominent disease-modifying factor is the gut microbiome which can exert both protective and detrimental effects on the nervous system in health and disease. An even better understanding of these factors will contribute to the development of individualized treatment approaches, a major research objective in the era of precision medicine. The current issue of Neuroprotection presents articles focusing on disease-modifying factors or novel treatment approaches for a broad spectrum of conditions. This provides a wide perspective but also novel insights into disease mechanisms and targeted treatment approaches. Priority has been given to articles reporting, reviewing or meta-analyzing clinical data as well as articles providing results of translationally relevant preclinical work.

Neuroprotection, December 2025

Pineal gland senescence: an emerging ageing-related pathology?

Mon, 26 Jan 2026 09:11:06 GMT

Emma Short, Ramzi Ajjan, Thomas M Barber, Sunil Bhandari, Paul Chazot, Jennifer L. Garrison, Anushka Goyal, Robert Huckstepp, Noordin Jamal, Venkateswarlu Kanamarlapudi, Alpar Lazar, Thomas Lee, Adriana A. S. Tavares, Jeremy J Tree, Jack Wellington, Stuart RG Calimport, Barry Bentley

An ageing-related pathology has recently been described as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline and that is evidenced by studies in humans. The pineal gland is a photo-neuroendocrine organ whose primary function is to produce and secrete melatonin in response to light-dark cycle environmental cues. The gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion. Pineal gland senescence describes the ageing-related decline in neuroendocrine function, with reduced secretion of melatonin, which may contribute to ageing-related sleep disorders and disruption of other circadian-driven physiological functions and may have secondary effects such as contributing to cognitive and mood disorders related to sleep disturbance.

Hormones, December 2025

Adenosine receptors in GtoPdb v.2025.4

Tue, 20 Jan 2026 09:00:00 GMT

Bertil B. Fredholm, Lauren May, Christa E. Müller, Joel Linden, Karl-Norbert Klotz, Kenneth A. Jacobson, Adriaan P. IJzerman, Rebecca Hills, Bruno G. Frenguelli, Gary L. Stiles

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [114]) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [155]. More recently, structures for the A_2B receptor [58, 48] and the A₃ receptor [279, 47] were elucidated. The A_2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank (www.rcsb.org). istradefylline, a selective A_2A receptor antagonist, is on the market for the treatment of Parkinson's disease, while caffeine's mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A₁ and A₃ receptors, have been explored chemically and structurally.

IUPHAR/BPS Guide to Pharmacology CITE, December 2025