A peptide-neurotensin conjugate that crosses the blood-brain barrier induces pharmacological hypothermia associated with anticonvulsant, neuroprotective, and anti-inflammatory properties following status epilepticus in mice
Year: 2025
Type: article
Abstract: ABSTRACT Preclinical and clinical studies show that mild to moderate hypothermia is neuroprotective in sudden cardiac arrest, ischemic stroke, perinatal hypoxia/ischemia, traumatic brain injury and seizures. Induction of hypothermia largely involves physical cooling therapies, which induce several clinical complications, while some molecules have shown to be efficient in pharmacologically induced hypothermia (PIH). Neurotensin (NT), a 13 amino-acid neuropeptide that regulates body temperature, interacts with various receptors to mediate its peripheral and central effects. NT induces PIH when administered intracerebrally. However, these effects are not observed if NT is administered peripherally, due to its rapid degradation and poor passage of the blood brain barrier (BBB). We conjugated NT to peptides that bind the low-density lipoprotein receptor (LDLR) to generate “vectorized” forms of NT with enhanced BBB permeability. We evaluated their effects in epileptic conditions following peripheral administration. One of these conjugates, VH-N412, displayed improved stability, binding potential to both the LDLR and NTSR-1, rodent/human cross-reactivity and improved brain distribution. In a mouse model of kainate (KA)-induced status epilepticus (SE), VH-N412 elicited rapid hypothermia associated with anticonvulsant effects, potent neuroprotection and reduced hippocampal inflammation. VH-N412 also reduced sprouting of the dentate gyrus mossy fibers and preserved learning and memory skills in the treated mice. In cultured hippocampal neurons, VH-N412 displayed temperature-independent neuroprotective properties. To the best of our knowledge, this is the first report describing the successful treatment of SE with PIH. In all, our results show that vectorized NT may elicit different neuroprotection mechanisms mediated either by hypothermia and/or by intrinsic neuroprotective properties.
Source: eLife
Authors: Lotfi Ferhat, Rabia Soussi, Maxime Masse, Grigorios Kyriatzis, Stéphane D. Girard, Fanny Gassiot, Nicolas Gaudin, Mathieu Laurencin, Anne Bernard, Angélique Bôle, Géraldine Ferracci, Maria Smirnova, François Roman, Vincent Dive, Salvatore Cisternino, Jamal Temsamani, Marion David, Pascaline Lécorché, Guillaume Jacquot, Michel Khrestchatisky
Institutions: Centre National de la Recherche Scientifique, Aix-Marseille Université, Institut de Neurophysiopathologie, Inserm, Université Paris Cité, Optimisation Thérapeutique en Neuropsychopharmacologie, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Paris-Saclay - Etablissement de Saclay, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funder: Agence Nationale de la Recherche
Awards: Development of nanobody-based vectors that cross the blood brain barrier via receptor-mediated transcytosis for brain delivery of imaging or therapeutic agents, G4076013790, Vectorisation (ciblage) d'agents thérapeutiques par des peptides-vecteurs dans le système nerveux central, Optimising CNS-targeted neurotensin-peptide-vector conjugates for induction of therapeutic hypothermia
OpenAlex ID: W4400720673