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P4‐155: Calpain and calpain‐activated caspase‐8 in amyloid‐b‐peptide toxicity: Attenuation by calpastatin overexpression
Author(s) -
Kosower Nechama S.,
Vaisid Tali,
Barnoy Sivia
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.722
Subject(s) - calpastatin , calpain , microbiology and biotechnology , cysteine protease , caspase , chemistry , signal transduction , proteases , caspase 3 , apoptosis , biochemistry , biology , programmed cell death , enzyme
Background: Impairment of the 2-oxoglutarate dehydrogenase complex (OGDHC) is associated with the glutamate accumulation, ROS production and neurodegeneration including Alzheimer disease and Wernike-Korsakoff syndrom. We showed that in neuronal cultures synthetic regulators of OGDHC are neuroprotective, reducing the glutamate excitotoxicity and excessive ROS. Here, we check physiological action of such regulator, succinyl phosphonate (SP), in rats stressed by hypoxia or ethanol, the known inducers of neurodegeneration. Methods: Normal or pregnancy-sensitized female rats experienced acute hypoxia in a decompression chamber with the atmospheric pressure decreased to 145 mm Hg. Alcohol treatment was performed on males by injections of 4.5 g/kg ethanol i.p. Intranasal application of SP in SP-treated groups or physiologic solution in reference groups was done 45-50 min before the hypoxia or ethanol exposure. Direct and delayed effects were determined within hours and the next day after treatments, respectively. The behavioral parameters were quantified in the open field, closed plus maze and light-dark chamber tests. Results: Behavior of control animals was generally not affected by SP. SP increased exploratory activity in males (by 40%, p1⁄40.05) and emotional strain in pregnant females (2-fold, p 0.05), with the latter effect preserved upon SPþhypoxia treatment. Behavioral impact of acute hypoxia was not pronounced, but sensitized by pregnancy. Low resistant pregnant rats tended to increase their hypoxia resistance after SP pretreatment which shifted the median time before collapsing from 129 to 178 s. 24H after, an increase in horizontal moving activity of hypoxic pregnant rats (by 13%, p<0.05) was abrogated in SPþhypoxia group. Ethanol caused much more profound behavioral changes. Compared to the ethanol-exposed males, combined SPþethanol treatment dose-dependently increased the alcohol-induced narcotic sleep (by up to 80%, p<0.05) and depression of the motor and exploratory activity 4H after awakening (11 parameters changed, p<0.01). These direct SP effects were followed by a better normalization of functions in 24H. The SPþethanol group exhibited decreased hyperactivity (by 31%, p<0.05), decreased anxiety index (by 22%, p<0.02) and increased activity in light (4-fold, p 0.05) versus the ethanol-treated males which remained significantly stressed. Conclusions: Metabolic depression through the OGDHC inhibition by SP in vivo protects from behavioral stress induced by hypoxia or ethanol.