000151427 001__ 151427
000151427 005__ 20250307114716.0
000151427 0247_ $$2doi$$a10.1111/bph.17448
000151427 0248_ $$2sideral$$a143103
000151427 037__ $$aART-2025-143103
000151427 041__ $$aeng
000151427 100__ $$0(orcid)0000-0002-7277-4318$$aMoreno-Martinez, Laura$$uUniversidad de Zaragoza
000151427 245__ $$aNovel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice
000151427 260__ $$c2025
000151427 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151427 5203_ $$aBackground and Purpose Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca2+ influx and buffering in early ALS‐affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca2+, as a therapeutic target. Experimental Approach A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)G93A mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival. Key Results Among the novel FKBP12 ligands, MP‐010 was chosen for its central nervous system availability and favourable in vitro pharmaco‐toxicological profile. Chronic administration of MP‐010 to SOD1G93A mice produced preservation of motor nerve conduction, with the 61‐mg·kg−1 dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP‐010 treatment significantly extended lifespan by an average of 10 days compared to vehicle. Conclusions and Implications FKBP12 ligands, particularly MP‐010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.
000151427 536__ $$9info:eu-repo/grantAgreement/ES/ISCIII/CB06-05-0041$$9info:eu-repo/grantAgreement/ES/ISCIII/CB06-05-1105$$9info:eu-repo/grantAgreement/ES/MICINN/PID2020-119780RB-100$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-140354OB-I00
000151427 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000151427 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151427 700__ $$aGaja-Capdevila, Núria
000151427 700__ $$aMosqueira-Martín, Laura
000151427 700__ $$aHerrando-Grabulosa, Mireia
000151427 700__ $$aRodriguez-Gomez, Laura
000151427 700__ $$aGonzalez-Imaz, Klaudia
000151427 700__ $$0(orcid)0000-0001-5193-7782$$aCalvo, Ana C.$$uUniversidad de Zaragoza
000151427 700__ $$aSagartzazu-Aizpurua, Maialen
000151427 700__ $$0(orcid)0000-0003-2436-7205$$aMoreno-García, Leticia
000151427 700__ $$aFuentes, Jose Manuel
000151427 700__ $$aAcevedo-Arozena, Abraham
000151427 700__ $$aAizpurua, Jesús María
000151427 700__ $$aMiranda, José Ignacio
000151427 700__ $$aLópez de Munain, Adolfo
000151427 700__ $$aVallejo-Illarramendi, Ainara
000151427 700__ $$aNavarro, Xavier
000151427 700__ $$0(orcid)0000-0001-5687-6704$$aOsta, Rosario$$uUniversidad de Zaragoza
000151427 700__ $$aGil-Bea, Francisco Javier
000151427 7102_ $$11001$$2420$$aUniversidad de Zaragoza$$bDpto. Anatom.,Embri.Genét.Ani.$$cÁrea Genética
000151427 7102_ $$11012$$2315$$aUniversidad de Zaragoza$$bDpto. Farmac.Fisiol.y Med.L.F.$$cÁrea Farmacología
000151427 773__ $$gEarly View (2025), [21 pp.]$$pBr. J. Pharmacol.$$tBRITISH JOURNAL OF PHARMACOLOGY$$x0007-1188
000151427 8564_ $$s5075165$$uhttps://zaguan.unizar.es/record/151427/files/texto_completo.pdf$$yVersión publicada
000151427 8564_ $$s1815187$$uhttps://zaguan.unizar.es/record/151427/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151427 909CO $$ooai:zaguan.unizar.es:151427$$particulos$$pdriver
000151427 951__ $$a2025-03-07-09:34:22
000151427 980__ $$aARTICLE