Abstract
Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin—all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.
Highlights
Taking into account the prominent polyuria that occurs in Li-treated rats, we examined the effect of Li on plasma sodium levels to exclude a condition of Li-induced hypernatremia
To exclude renal fibrosis, we examined the effect of Li treatment on kidney weight
Given that low-dose aspirin has been reported to exert anti-inflammatory effects [119,120] along with the well-established involvement of inflammation in the pathophysiology of Bipolar disorder (BD) [45,46,47,48,49], we hypothesized that co-administration of low-dose aspirin and Li could enable reduction in the required Li dose to gain mood stabilization
Summary
Bipolar disorder (BD) is a chronic psychiatric disorder characterized by repeated manic, hypomanic, and depressive episodes [1,2,3,4,5]. It affects 1–2% of the general population [1,2,6]. Is recognized as one of the leading disability causes worldwide, associated with significant impairment in work, family, and social life, beyond the acute phases of the illness [2,7]. Cardiovascular disease is the leading cause of death in BD [14], with patients having a two-fold increased risk of mortality from
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