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In Alzheimer's brain, astrocytic dysfunction contributes significantly to the rapid progression of the disease pathology. A\u03b2 deposition induces oxidative alterations in the astrocytic glutamate transporter EAAT2, leading to impaired glutamate uptake and elevated extracellular glutamate levels, which drive excitotoxicity. This disruption adversely impacts synaptic plasticity, neuronal survival, and cognitive integrity, highlighting the pivotal role of astrocytes in the early phases of AD. Restoration of EAAT2 function is critical to mitigating disease progression and preserving cognitive function. Through in silico analyses, three potential allosteric modulators of EAAT2 were identified. These compounds were further tested on A\u03b2\u2010intoxicated primary neuronal\u2010astrocyte mixed cultures, with their efficacy evaluated via immunoblotting for EAAT2 expression, in\u00a0vitro glutamate assays for functional assessment, and morphological analyses of astrocytes and neurons using GFAP and \u03b2\u2010III tubulin markers. Notably, PTID and NDHP significantly enhanced EAAT2 expression and function, reducing extracellular glutamate levels and ameliorating excitotoxic damage. Moreover, these compounds demonstrated neuroprotective effects by promoting dendritic growth and branching in \u03b2\u2010III tubulin\u2010positive neurons. Immunocytochemical analyses further revealed an increased number of \u03b2\u2010III tubulin and GFAP\u2010positive cells, suggesting that PTID and NDHP not only improved neuronal integrity but also supported astrocytic resilience and functionality. The findings of the current study underscore the critical role of astrocytes in glutamate homeostasis and cognition, showcasing the therapeutic potential of EAAT2 allosteric modulators, particularly PTID and NDHP, in alleviating A\u03b2\u2010induced neurotoxicity. By enhancing EAAT2 function, these modulators restore astrocytic support for synaptic health, offering a promising avenue for addressing cognitive decline in AD.<\/jats:p>","DOI":"10.1111\/cbdd.70232","type":"journal-article","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T12:20:37Z","timestamp":1767442837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Based Identified EAAT2 Transporter Activator Attenuates Amyloid\u2010\u03b2 Induced Excitotoxicity in Primary Neuronal\u2010Astroglial Mixed Culture by Ameliorating Glutamate Clearance"],"prefix":"10.1111","volume":"107","author":[{"given":"Chennu","family":"Manisha","sequence":"first","affiliation":[{"name":"Department of Pharmacology JSS College of Pharmacy, JSS Academy of Higher Education &amp; Research  Ooty Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anusa","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Neuroscience Unit Jawaharlal Nehru Centre for Advanced Scientific Research  Bengaluru Karnataka India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagarjuna","family":"Palathoti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education &amp; Research  Ooty Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jubie","family":"Selvaraj","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education &amp; Research  Ooty Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. 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