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  • Hakon, JakobLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine (författare)

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity

  • Artikel/kapitelEngelska2024

Förlag, utgivningsår, omfång ...

  • 2024

Nummerbeteckningar

  • LIBRIS-ID:oai:lup.lub.lu.se:10291d5e-8497-4039-91d0-3c5085fbad3c
  • https://lup.lub.lu.se/record/10291d5e-8497-4039-91d0-3c5085fbad3cURI
  • https://doi.org/10.1093/brain/awad293DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:art swepub-publicationtype
  • Ämneskategori:ref swepub-contenttype

Anmärkningar

  • Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function, and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischemia. Using multiple behavioral tests we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam, and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172, and accelerated in mGluR5 KO mice compared to wild-type mice. After stroke, multisensory stimulation by enriched environments (EE) enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in EE-mediated recovery. Additionally, MTEP treatment in conjunction with EE housing provided an additive recovery enhancement compared to either MTEP or EE alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Quattromani, Miriana JLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-mqu (författare)
  • Sjölund, CarinLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUBIN Lab- Lunds laboratorium för neurokirurgisk hjärnskadeforskning,Forskargrupper vid Lunds universitet,Laboratory for Experimental Brain Research,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,LUBIN Lab- Lund Brain Injury laboratory for Neurosurgical research,Lund University Research Groups(Swepub:lu)expb-csj (författare)
  • Talhada, DanielaLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-det (författare)
  • Kim, BungchanWashington State University (författare)
  • Moyanova, SlaviankaIstituto Neurologico Mediterraneo Neuromed (författare)
  • Mastroiacovo, FedericaIstituto Neurologico Mediterraneo Neuromed (författare)
  • Di Menna, LuisaIstituto Neurologico Mediterraneo Neuromed (författare)
  • Olsson, RogerLund University,Lunds universitet,NanoLund: Centre for Nanoscience,Annan verksamhet, LTH,Lunds Tekniska Högskola,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,LTH profilområde: Nanovetenskap och halvledarteknologi,LTH profilområden,LU profilområde: Ljus och material,Lunds universitets profilområden,Other operations, LTH,Faculty of Engineering, LTH,Chemical Biology and Therapeutics,Lund University Research Groups,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,LUCC: Lund University Cancer Centre,Other Strong Research Environments,LTH Profile Area: Nanoscience and Semiconductor Technology,LTH Profile areas,Faculty of Engineering, LTH,LU Profile Area: Light and Materials,Lund University Profile areas(Swepub:lu)med-reo (författare)
  • Englund, ElisabetLund University,Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Patologi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Pathology, Lund,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)pat-een (författare)
  • Nicoletti, FerdinandoSapienza University of Rome,Istituto Neurologico Mediterraneo Neuromed (författare)
  • Ruscher, KarstenLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUBIN Lab- Lunds laboratorium för neurokirurgisk hjärnskadeforskning,Forskargrupper vid Lunds universitet,Laboratory for Experimental Brain Research,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,LUBIN Lab- Lund Brain Injury laboratory for Neurosurgical research,Lund University Research Groups(Swepub:lu)med-ktr (författare)
  • Bauer, Adam QWashington State University (författare)
  • Wieloch, TadeuszLund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)efor-twi (författare)
  • NeurokirurgiSektion IV (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Brain : a journal of neurology147:1, s. 186-2001460-2156

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