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 - Archive ouverte HAL
Pré-Publication, Document De Travail Année : 2024

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

Lotfi Ferhat
Rabia Soussi
  • Fonction : Auteur
Maxime Masse
  • Fonction : Auteur
Stephane Girard
Fanny Gassiot
  • Fonction : Auteur
Nicolas Gaudin
  • Fonction : Auteur
Mathieu Laurencin
  • Fonction : Auteur
Maria Smirnova
  • Fonction : Auteur
Vincent Dive
  • Fonction : Auteur
Salvatore Cisternino
Jamal Temsamani
  • Fonction : Auteur
Marion David
  • Fonction : Auteur
Pascaline Lecorche
  • Fonction : Auteur
Guillaume Jacquot
  • Fonction : Auteur

Résumé

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.
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hal-04752312 , version 1 (24-10-2024)

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Lotfi Ferhat, Rabia Soussi, Maxime Masse, Grigorios Kyriatzis, Stephane Girard, et al.. 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. 2024. ⟨hal-04752312⟩
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