title: Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.
abstract: Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH.
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi 110054, India.
authors.forename: H
authors.initials: H
authors.lastname: Kauser
authors.forename: S
authors.initials: S
authors.lastname: Sahu
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: U
authors.initials: U
authors.lastname: Panjwani
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D016316:Guanfacine / Q000627:therapeutic use*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D008570:Memory, Short-Term / Q000187:drug effects*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D016316:Guanfacine
keywords: Apoptosis; DAT; GFC; Guanfacine; HH; Hypobaric hypoxia; Neurodegeneration; PFC; Prefrontal cortex; SWM; Spatial working memory; delayed alternation task; hypobaric hypoxia; prefrontal cortex; spatial working memory