کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10299078 | 539684 | 2014 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
روانپزشکی بیولوژیکی
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چکیده انگلیسی
Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-d-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50 mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50 mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5 mg/kg ip) hyperactivity. PGW5 (25 mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50 mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. Conclusions: PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Neuropsychopharmacology - Volume 24, Issue 3, March 2014, Pages 425-436
Journal: European Neuropsychopharmacology - Volume 24, Issue 3, March 2014, Pages 425-436
نویسندگان
Irit Gil-Ad, Moshe Portnoy, Igor Tarasenko, Miri Bidder, Maria Kramer, Michal Taler, Abraham Weizman,