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JAK4D is a first-in-class thyrotropin releasing hormone (TRH) analogue that overcomes the pharmacological limitations of thyrotropin releasing hormone and enables delivery of the long-recognized multifactorial neurotherapeutic actions of thyrotropin releasing hormone without inducing endocrine side effects. JAK4D is demonstrated to be neuroprotective and significantly reduce excitotoxic-induced hippocampal-dependent memory deficits in rat. In the present study, we used the scopolamine challenge test coupled with the novel object recognition test to evaluate the effect of JAK4D on scopolamine-induced recognition memory deficits in the male, Lister-Hooded rat. Scopolamine administration has been shown by others to mimic cholinergic and brain network disruption in neurodegenerative diseases. Although the scopolamine challenge test does not fully replicate the pathophysiology of neurodegenerative disease, such as Alzheimer\u2019s disease, it is a well-recognized acute pharmacological model for assessing the ability of pharmacological interventions to counteract memory deficits relevant to neurodegenerative diseases. In this model of cholinergic dysfunction, we also assessed the effects of thyrotropin releasing hormone, taltirelin (a degradation-stabilized thyrotropin releasing hormone analogue) and the acetylcholinesterase inhibitor, donepezil, as a positive reference compound. The discrimination (d2) index was used as the primary measure to assess the effect of treatment on scopolamine-induced performance deficit in the novel object recognition test. d2 is a standard well-recognized measure of discrimination between a novel and familiar object in the novel object recognition test, which advantageously takes into account individual differences in exploration levels. Across all investigations, JAK4D (1\u2005mg\/kg i.p.) significantly reversed scopolamine-induced recognition memory impairment (P = 0.0274, P = 0.0002, P &amp;lt; 0.0001). The degree of reversal of scopolamine-induced memory deficits by JAK4D (1\u2005mg\/kg i.p.) was indistinguishable from that observed for donepezil (0.1\u2005mg\/kg p.o.) (P = 0.026). Subcutaneously administered JAK4D (0.3\u201310.0\u2005mg\/kg) also significantly reversed this deficit (P = 0.0432\u20130.0021). Furthermore, similar pro-cognitive effects were exerted by thyrotropin releasing hormone (5\u2005mg\/kg i.p., P = 0.0055) and taltirelin (10\u2005mg\/kg p.o., P = 0.0002). Together, these results underscore the relevance of the central thyrotropin releasing hormone signalling system for the treatment of memory impairment. Data from the current study provide further evidence in support of the potential of JAK4D as a novel therapeutic for cognitive deficits in neurodegenerative diseases.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag006","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T12:46:28Z","timestamp":1768394788000},"source":"Crossref","is-referenced-by-count":0,"title":["JAK4D, a first-in-class thyrotropin-releasing hormone analogue, reverses scopolamine-induced memory deficits"],"prefix":"10.1093","volume":"8","author":[{"given":"Roisin","family":"McMackin","sequence":"first","affiliation":[{"name":"Academic Unit of Neurology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin , Dublin 2 D02 R590 ,","place":["Ireland"]},{"name":"Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin , Dublin 2 D02 R590 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