Chronic Inflammation by LPS Aggravates Rotenone Neurotoxicity and Circadian Clock Disruption in Rats

In this chapter, we investigated when such a condition happens in rats and whether such low-grade neuroinflammation might exacerbate rotenone (ROT) neurotoxicity and impair circadian clock gene/protein expressions. Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by motor dysfunction. Aging is the greatest risk factor for developing PD. Recent molecular genetic studies have revealed that genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Parkinson's disease (PD) was induced in mice after a single treatment with lipopolysaccharide (LPS) through low-grade neuroinflammation many months later. Three months after receiving two injections of LPS (2.5-7.5 mg/kg) in male rats, neuroinflammation and dopamine cell loss were visible. Rats were given modest doses of ROT (0.5 mg/kg, sc, 5 times/week for 4 weeks) seven months after receiving a single injection of LPS (5 mg/kg) to study the effects of low-grade neuroinflammation on ROT toxicity. LPS plus ROT produced more pronounced non-motor and motor dysfunctions than LPS or ROT alone in Open-field, Elevated plus maze, Y-maze and Rotarods tests, and decreased mitochondrial complex 1 activity, together with aggravated neuroinflammation and neuron loss. LPS, ROT, and LPS + ROT groups showed lower expression of the clock core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock), and neuronal PAS domain protein-2 (Npas2). The expressions of circadian feedback genes Periods (Per1 and Per2) were also reduced, but Cryptochromes (Cry1 and Cry2) were unaltered. The circadian clock target genes nuclear receptor Rev-Erb (Nr1d1), and D-box-binding protein (Dbp) expressions were also decreased. Consistent with the transcript levels, circadian clock protein BMAL1, CLOCK, NR1D1 and DBP were also decreased. LPS-induced chronic low-grade neuroinflammation potentiated ROT neurotoxicity and disrupted circadian clock gene/protein expression, suggesting a role of disrupted circadian in PD development and progression.