Cognitive effects of the GSK-3 inhibitor “lithium” in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy

• Published in: Neurotoxicology (Park Forest South) 2021-03, Vol.83, p.77-88
• Main Authors: Ebeid, Mai A., Habib, Mohamed Z., Mohamed, Ahmed M., Faramawy, Yasser el, Saad, Sherin S.T., El-Kharashi, Omnyah A., El Magdoub, Hekmat M., Abd-Alkhalek, Hadwa A., Aboul-Fotouh, Sawsan, Abdel-Tawab, Ahmed M.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Cerebral Cortex - physiopathology; Chronic Disease; Chronic mild stress; Cognition; Cognition - drug effects; Cognitive ability; Cognitive Dysfunction - enzymology; Cognitive Dysfunction - etiology; Cognitive Dysfunction - physiopathology; Cognitive Dysfunction - prevention & control; Depression - enzymology; Depression - etiology; Depression - physiopathology; Depression - prevention & control; Disease Models, Animal; Dosage; Encephalitis - enzymology; Encephalitis - etiology; Encephalitis - physiopathology; Encephalitis - prevention & control; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Glycogens; Hippocampus; Hippocampus - drug effects; Hippocampus - enzymology; Hippocampus - physiopathology; Immune response; Immune system; Inflammation; Inflammation Mediators - metabolism; Inhibition (psychology); Kinases; Lipopolysaccharide; Lipopolysaccharides; Lithium; Lithium Chloride - pharmacology; Male; Mental depression; Neurodegenerative diseases; Neuroinflammation; Overexpression; Pathogenesis; Phosphorylation; Prefrontal cortex; Protein Kinase Inhibitors - pharmacology; Psychological stress; Rats; Rats, Wistar; Schedules; Spatial discrimination learning; Spatial Learning - drug effects; Stress, Psychological - complications; Stress, Psychological - psychology; Survival; Tau protein; tau Proteins - metabolism; Tauopathies - enzymology; Tauopathies - etiology; Tauopathies - physiopathology; Tauopathies - prevention & control; Tauopathy
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2020.12.016

•Repeated LPS pre challenge abrogated CMS-induced neuroinflammation, depressive-like behavior and cognitive dysfunction.•LPS pre challenge exaggerated CMS-induced GSK-3β over-expression and hyperphosphorylated tau accumulation.•Lithium ameliorated CMS and LPS/CMS-induced cognitive deficits, tau pathology and neuroinflammation.•Prior low-dose immune challenge could help to buffer subsequent inflammatory damage and preserve neuronal functioning. Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3β (GSK-3β) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3β expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3β over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3β inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.