Multi-target neuroprotective compound exhibits EAAT2-modulating and alzheimer’s pathology–attenuating effects in in vitro and in vivo models

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dc.authorid0000-0002-1504-7480
dc.authorid0000-0001-8124-9315
dc.authorid0000-0001-8124-9315
dc.authorid0009-0003-9288-4789
dc.authorid0000-0002-8919-6673
dc.authorid0000-0003-0558-0086
dc.authorid0000-0002-4810-6352
dc.authorid0000-0001-5045-5095
dc.authorid0000-0002-7046-8990
dc.contributor.authorHacımüftüoğlu, Ahmet
dc.contributor.authorSaraçoğlu, Nurullah
dc.contributor.authorSaffour, Sana
dc.contributor.authorAbad, Nadeem
dc.contributor.authorKesgun, Yunus
dc.contributor.authorZegheb, Nadjiba
dc.contributor.authorGündeğer, Ersin
dc.contributor.authorYeşilyurt, Fatma
dc.contributor.authorAtaş, Merve Nur
dc.contributor.authorTürkez, Hasan
dc.date.accessioned2026-05-03T14:06:33Z
dc.date.available2026-05-03T14:06:33Z
dc.date.issued2026
dc.departmentFakülteler, Eczacılık Fakültesi, Eczacılık Meslek Bilimleri Bölümü, Biyokimya Ana Bilim Dalı
dc.description.abstractAlzheimer’s disease (AD) is a debilitating neuro degenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitat ing the development of innovative multitarget therapeutic strategies. Here, we present N3 ,N5 -bis(2-(5-methoxy-1H-indol-3- yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxa mide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer’s model in female Sprague−Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.
dc.identifier.citationHacımüftüoğlu, A., Saraçoğlu, N., Saffour, S., Abad, N., Kesgun, Y., Zegheb, N., Gündeğer, E., Yeşilyurt, F., Ataş, M. N., & Türkez, H. (2026). Multi-target neuroprotective compound exhibits EAAT2-modulating and alzheimer’s pathology–attenuating effects in in vitro and in vivo models. ACS Chemical Neuroscience, https://doi.org/10.1021/acschemneuro.5c00873
dc.identifier.doi10.1021/acschemneuro.5c00873
dc.identifier.issn1948-7193
dc.identifier.pmidPMID: 42051019
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1021/acschemneuro.5c00873
dc.identifier.urihttps://hdl.handle.net/20.500.13055/1465
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.indekslendigikaynak.otherSCI-E - Science Citation Index Expanded
dc.institutionauthorGündeğer, Ersin
dc.institutionauthorid0000-0002-4810-6352
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.ispartofACS Chemical Neuroscience
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectNeurodegeneration
dc.subjectGlutamate Excitotoxicity
dc.subjectTau Pathology
dc.subjectΒ-Amyloid Pathology
dc.subjectOxidative Stress
dc.titleMulti-target neuroprotective compound exhibits EAAT2-modulating and alzheimer’s pathology–attenuating effects in in vitro and in vivo models
dc.typeArticle
dspace.entity.typePublication

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