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Increased hippocampal neurogenesis and prolonged amelioration of memory deficits by chronic oxotremorine treatment in a rodent model of Alzheimer’s disease.

Nair DV, Al-Badri MM, Rogido M, Pacheco-Quinto J, Peng H, Iacono D, Eckman CB, Eckman EA (2013) Increased hippocampal neurogenesis and prolonged amelioration of memory deficits by chronic oxotremorine treatment in a rodent model of Alzheimer’s disease. Neuroscience 2013 Abstracts 599.01. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic transmission plays a predominant role in memory processes, and loss of basal forebrain cholinergic innervation of the hippocampus has been correlated with memory impairment in Alzheimer’s disease (AD), as well as in decreased hippocampal neurogenesis in rats. Using a rat model of AD-like basal forebrain cholinergic cell loss, our lab has previously shown that central administration of a muscarinic receptor agonist, oxotremorine, for 4 weeks could reverse the spatial working memory deficit triggered by cholinergic denervation and induce hippocampal neurogenesis. The goal of the present study was to examine whether effects of chronic oxotremorine treatment persist beyond the treatment period, possibly indicating a disease-altering effect of the drug, particularly on memory function. Adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP), to induce AD-like basal forebrain cholinergic cell loss. After a 5 week recovery period, the rats then received 8 weeks of icv infusion of either oxotremorine or saline via osmotic minipump. Behavioral testing in a partially baited radial arm maze began 4 weeks after oxotremorine treatment was discontinued. To analyze cell proliferation, rats received intraperitoneal injections of BrdU either during the first 2 weeks of treatment, or at the end of behavioral testing. One month after oxotremorine treatment was discontinued, SAP-lesioned rats showed persistent improvements in radial arm maze acquisition, such that there was no difference in performance among sham/saline, sham/oxotremorine, and SAP/oxotremorine groups. SAP-lesioned rats treated with saline, however, still showed significant impairments compared to the other groups. Neuropathological and stereological analyses of these brains are ongoing, including analysis of hippocampal neurogenesis and neuronal cell counts in both basal forebrain and hippocampal regions. In a parallel cohort of rats analyzed at the end of the 8 week treatment period, initial results indicate no change in cholinergic cell density but a modest increase in the number of GABAergic cells in medial septum/diagonal band of lesioned rats treated with oxotremorine compared to saline. In the dentate gyrus (DG) of the hippocampus, increased numbers of cells labeled with BrdU during the first 2 weeks of treatment persisted to the end of the experiment, with an overall 1.5-fold increase in the number of BrdU labeled cells detected in the DG. These findings demonstrate that muscarinic stimulation is a promising target in the development of drugs to treat disorders involving cholinergic loss, such as AD.

Related Products: 192-IgG-SAP (Cat. #IT-01)