Minocycline restores cognitive-relative altered proteins in young bile duct-ligated rat prefrontal cortex
Introduction
Hepatic encephalopathy (HE) is an important and complex neuropsychiatric syndrome caused by liver diseases [1], [2]. According to the International Society for Hepatic Encephalopathy and Nitrogen Metabolism, the bile duct ligation (BDL) model can be used to study chronic liver failure associated with HE [3]. BDL in rats is characterized with chronic liver failure accompanied with brain dysfunction, including increased oxidative stress in the brain [4], [5], [6] and cognition impairment [4], [7]. In particular, cognitive dysfunction is one of the most challenging complications of HE, with no specific treatments currently available.
Minocycline-an anti-oxidative, semi-synthetic, second-generation tetracycline derivative- effectively inhibits microglial activation and the associated neuroinflammation in HE and several other pathological conditions [8], [9], [10], [11]. Interestingly, minocycline can readily cross the blood-brain barrier [12]. Furthermore, minocycline exhibits anti-oxidant properties [13] and may be used to rescue cognitive impairments in brain disorders [14].
BDL-related genes, proteins, and pathways in the brain remain largely unknown. Comparative and comprehensive proteomic analyses have paved way for new molecular tools and interventions. These analyses may reveal the mechanisms underlying BDL-induced brain pathologies and cognition deficits.
In this study, we used proteomic tools to study the proteomic profile of the prefrontal cortex of young BDL rats. We investigated the expression of cognition-related proteins following BDL treatment and evaluated the effect of minocycline on these proteins and spatial memory.
Section snippets
Animals
All animal experiments were performed according to the Guidelines for Animal Experiments of Chang Gung Memorial Hospital. Sprague-Dawley rats were used throughout the experiment. The delivery day was designated as postnatal day 0 (PND 0). Only male rats were used to avoid the sex effects on spatial memory and oxidative stress. At PND17, an age equivalent to human early childhood [15], male Sprague-Dawley rats which average weight about 45–50 ± 5 g from the same dam were randomly assigned to 2
Morris water maze and plasma biochemistry parameters
The water maze test revealed that all rats were able to learn to find the platform and that there was no significant difference in swim velocity between the different treatment groups at any time (p > 0.1). Two-factor ANOVA revealed significant differences among the groups for the number of trial blocks needed to learn to escape by swimming with visual cues (p < 0.01). Escape latencies improved over time in all four groups, as observed by a significant effect of day (p < 0.01), indicating that
Discussions
Our study identified changes in the prefrontal cortex proteins with 2D/LC-MS/MS and the significant findings are as follows: 1) CRMP2 was upregulated and NME2 and MnSOD were downregulated in BDL rats; 2) minocycline treatment restored CRMP2 and NME2 protein levels, BDNF mRNA levels, and MnSOD activity in BDL rats to comparable levels in SHAM rats; and 3) minocycline rescued the spatial learning ability in BDL rats.
The prefrontal cortex organizes multiple pieces of information in the working
Acknowledgement
This work was supported by Grant CMRPG8F0182 from Chang Gung Memorial Hospital, Kaohsiung, Taiwan to Dr. Li-Tung Huang. We thank the help of the Genomics & Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
References (44)
- et al.
Hepatic encephalopathy: clinical aspects and pathogenetic concept
Arch. Biochem. Biophys.
(2013) - et al.
Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy
Arch. Biochem. Biophys.
(2013) - et al.
Minocycline attenuates oxidative/nitrosative stress and cerebral complications of acute liver failure in rats
Neurochem. Int.
(2009) - et al.
Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice
Behav. Brain Res.
(2013) Trajectories of brain development: point of vulnerability or window of opportunity?
Neurosci. Biobehav. Rev.
(2003)- et al.
An old method facing a new challenge: re-visiting housekeeping proteins as internal reference control for neuroscience research
Life Sci.
(2013) - et al.
Post-translational processing of Drosophila nucleoside diphosphate kinase
Biochem. Biophys. Res. Commun.
(2002) - et al.
The effects of intra-dorsal hippocampus infusion of pregnenolone sulfate on memory function and hippocampal BDNF mRNA expression of biliary cirrhosis-induced memory impairment in rats
Neuroscience
(2015) - et al.
GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity
Cell
(2005) - et al.
Down-regulation of BDNF mRNA, with no effect on trkB or glucocorticoid receptor m RNAs, in the porcine hippocampus after acute dexamethasone treatment
Res. Vet. Sci.
(2001)