Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain

Abstract

With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. However, the mechanisms underlying the neurological complications are least elucidated. We have recently reported a highly reproducible mice model of CKD induced by high adenine diet, which exhibited psychomotor behavioral abnormalities and blood-brain barrier disruption. In the present study, using the mice model, we have investigated psycho-motor and cognitive behaviour, and the neurochemical and histopathological alterations in brain relevant to the observed behavioural abnormalities. The results demonstrate global loss of Acetylcholinesterase activity, and decrease in neuronal arborisation and dendritic spine density in discrete brain regions, of the CKD mice. Oxidative stress, inflammation, and mitochondrial dysfunctions were found in specific brain regions of the mice, which have been regarded as the underlying causes of the observed neurochemical and histopathological alterations. Thus, the present study is of immense importance, and has therapeutic implications in the management of CKD-associated neurological complications.

Neuropsychiatric Disorders in Chronic Kidney Disease

“…More recently, in an experimental study with CKD induced by 4 weeks of adenine-rich diet, animals developed depressive-like behavior, locomotor alterations, and cognitive decline. In parallel with these behavioral and cognitive changes, animals also had decreased catalase and increased superoxide dismutase activities, elevated lipid peroxidation, and enhanced NOS-active neurons and dysfunction of mitochondrial complexes in key areas like striatum, substantia nigra, cortex, and hippocampus (Mazumder et al, 2019). Altogether, these experimental studies support the involvement of oxidative stress in neuropsychiatric disorders secondary to CKD.…”

Behavioral Changes During Development of Chronic Kidney Disease in Rats

“…Cognitive decline is one of the most common neurological symptoms in CKD patients (12-15, 17, 30). Numerous experiments have confirmed deficit in spatial- (23,45), recognition- (21,42,(45)(46)(47), as well as aversive-related memory (46)(47)(48) in CKD animals. On the contrary, there are also some experiments which failed to show memory-impairing effect of CKD (24,49).…”

“…It has been shown that mild CKD may lead to activation of limbic system, central sympathetic, stress-and pain-related brain areas (31). Some CKD-related neurological complications have been attributed to impaired permeability of the blood-brain barrier (22,32,33), neuroinflammation, and oxidative stress (21)(22)(23). Neurotoxicity induced by numerous substances, such as urea, accumulated in blood during kidney disease (34)(35)(36) might also play a role (33).…”

“…However, animal experiments have brought contradictory results. Although depressive-like behavior was found in some animal models of CKD (21,32), it has been shown several times that animals with CKD exhibit decreased emotionality (39) and low-level anxiety (24,32,42). The anxiolytic effect of CKD was indicated mainly by reduced time spent in the dark chamber of light/dark box, while it was not manifested in other tests assessing anxiety, such as elevated plus maze or open field test (24,32,42).…”

“…Individual's quality of life can be further decreased by sexual dysfunction (7), neurological and mental disorders including anxiety and depression (7)(8)(9)(10)(11), as well as cognitive impairment (12)(13)(14)(15)(16)(17) or epileptic seizures (18), all of which lead to increased socio-economic burden of affected people (19). Although, the exact pathophysiological mechanisms underlying the neurological complications of CKD remain unclear, there are several factors that might play a role, e.g., uremic encephalopathy (20), oxidative stress (21)(22)(23) and inflammation (21,22).…”