Project name: Cellular Therapeutic Approaches for Regenerative Stroke

Acronym: CELEST

Contracting authority: UEFISCDI

Project code: PN-II-PT-PCCA-2011-3.1-0222

Project number: 80/2012

Start date: 02.07.2012

Term: 36 months

Abstract: We and others have shown that potential mechanisms for self-repair also operate in the post-ischemic aged brain. The major factors involving the loss of regenerative capacity in the aged brain are an age-related decrease in neurogenesis, and a loss of environmental hostility disturbing regeneration and migration of neuronal precursors toward the ischemic lesion. To date, all monotherapeutic attempts to prevent or lessen brain damage following stroke have failed. In view of our findings that stroke impacts a wide range of systems in an age-dependent manner, from CNS physiology to CNS regeneration and plasticity, the failure of therapies aimed at only a single target system is perhaps inevitable. We hypothesize that a multi-stage, multimodal treatment in aged animals may be more likely to produce positive results. Dysregulation of the inflammatory response in the aged brain thus may be one reason for the severity of the damage as well as the brain’s intractability to neuroprotective therapies in the elderly. Therefore the first step of our multimodal therapeutic strategy is to limit inflammation and achieve neuroprotection during the acute and subacute phase of stroke by whole body cooling. The aged brain is particularly refractant to growth phenomena after injuries. Therefore in the second phase of our therapeutical strategy the major goal is to create a growth-permissive environment by transplatation/administration of bone marrow-derived mesenchymal cells, which are versatile cells and therefore well-suited to achieve our objective. Finally, we hypothesize that exogenously administered neural stem cells (NSCs) into a growth-permissive environment created in the previous steps in aged rats at two weeks after stroke will augment the prospects of histological and behavioral recuperation after stroke. Overall the targets identified will be used to develop new pre-clinical therapeutic strategies aimed at improving recuperation after stroke in the aged subjects. 

Abstarct (ROM): Alaturi de altii, noi am demonstrat ca mecanismele potentiale de auto-reparare functioneaza si pentru creierul imbatranit post-ischemic. Factorii majori care duc la pierderea capacitatii de regenerare in creierul imbatranit sunt scaderea neurogenezei corelata cu varsta si reducerea factorilor de mediu prielnici, fapt care perturba regenerarea si migrarea precursorilor neuronali spre zona de leziune ischemica. Pana in acest moment, toate incercarile monoterapeutice de a preveni si a micsora leziunile cerebrale ce urmeaza unui atac cerebral au esuat. In ceea ce priveste descoperirile noastre, conform carora atacul cerebral are impact asupra unui numar ridicat de sisteme biologice, intr-un ritm proportional cu varsta, de la fiziologia SNC pana la regenerarea si plasticitatea SNC, esecul monoterapiilor este probabil inevitabil. Credem ca la mai multe nivele, tratamentul multimodal la animalele imbatranite este cel mai probabil sa produca rezultate pozitive. Lipsa regularitatii raspunsului inflamator la creierul imbatranit poate fi astfel una dintre cauzele severitatii leziunii, pe langa lipsa raspunsului creierului la terapiile de protectie neuronala pentru cei in varsta. In consecinta, primul pas al strategiei noastre de terapie multimodala este sa limitam inflamatia si sa obtinem protectia neuronala in timpul fazelor acuta si subacuta ale atacului prin scaderea temperaturii intregului corp. Creierul imbatranit este in mod special refractant la fenomenele de crestere dupa injurii. Asadar in faza a doua a strategiei noastre terapeutice scopul principal este ca cream un mediu propice cresterii neuronale prin transplantul / administrarea de celule mezenchimale prelevate din maduva osoasa, care sunt versatile si deci potrivite pentru atingerea obiectivului nostru. Spre sfarsit, consideram ca celulele stem neuronale administrate exogen (CSN) intr-un mediu de cultura, creat in etapele anterioare in sobolanii maturi, la doua saptamani dupa atac, vor amplifica posibilitatea recuperarii comportamentale si histologice, in urma atacului cerebral. In concluzie, tintele identificate vor fi folosite pentru a crea strategii terapeutice pre-clinice noi pentru a imbunatati recuperarea in urma atacului la subiectii imbatraniti.