Short-term treatment with the GABAAreceptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome

Autor:	Bayarsaikhan Chuluun, D Warrier, Daniel Z. Wetmore, Martina Blank, H C Heller, Paul S. Buckmaster, Craig C. Garner, Damien Colas
Rok vydání:	2013
Předmět:	Pharmacology Down syndrome Seizure threshold medicine.diagnostic_test GABAA receptor Antagonist Hippocampus Electroencephalography medicine.disease Neuroplasticity medicine Effects of sleep deprivation on cognitive performance Psychology
Zdroj:	British Journal of Pharmacology. 169:963-973
ISSN:	0007-1188
DOI:	10.1111/bph.12169
Popis:	Background and Purpose Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans. Experimental Approach Long-term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short-term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio-marker of the treatment. Key Results PTZ has a wide therapeutic window (0.03–3 mg·kg−1) that is >10–1000-fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short-term, low, chronic dose regimens of pentylenetetrazole elicited long-lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice. Conclusions and Implications Low doses of pentylenetetrazole were safe, produced long-lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::fba5ddb74c3d06d8ee354475e4030327 https://doi.org/10.1111/bph.12169 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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