Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

Abstract

A single injection of LPS produced low-grade neuroinflammation leading to Parkinson’s disease (PD) in mice several months later. Whether such a phenomenon occurs in rats and whether such low-grade neuroinflammation would aggravate rotenone (ROT) neurotoxicity and disrupts circadian clock gene/protein expressions were examined in this study. Male rats were given two injections of LPS (2.5–7.5 mg/kg), and neuroinflammation and dopamine neuron loss were evident 3 months later. Seven months after a single LPS (5 mg/kg) injection, rats received low doses of ROT (0.5 mg/kg, sc, 5 times/week for 4 weeks) to examine low-grade neuroinflammation on ROT toxicity. LPS plus ROT produced more pronounced non-motor and motor dysfunctions than LPS or ROT alone in behavioral tests, and decreased mitochondrial complex 1 activity, together with aggravated neuroinflammation and neuron loss. The expressions of clock core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock), and neuronal PAS domain protein-2 (Npas2) were decreased in LPS, ROT and LPS plus ROT groups. The expressions of circadian feedback genes Periods (Per1 and Per2) were also decreased, but Cryptochromes (Cry1 and Cry2) were unaltered. The circadian clock target genes nuclear receptor Rev-Erbα (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. Thus, 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.

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

“…Circadian-disrupted mice had severe neuroinflammation and a greater degradation of motor skills, indicating that circadian dysfunction is a potential risk factor for PD. This effect was recapitulated in a rat model, where PD pathology was induced or exacerbated in one of three ways: by injection of lipopolysaccharide, injection of rotenone, or injection of both reagents ( Li et al, 2019 ). All three groups exhibited similar loss of dopaminergic neurons and neuroinflammation.…”

Chronic Manganese Administration with Longer Intervals Between Injections Produced Neurotoxicity and Hepatotoxicity in Rats

“…2 b). These results demonstrated that Mn injections induced chronic neuroinflammation in rats causing delayed loss of THir neurons in SNpc, a brain region sensitive to Mn and LPS intoxication [ 25 , 26 ]. It should be noted that in this study, 20% rats in the Mn 2+ 5 mg/kg group died, which could have more severe injury than surviving rats.…”

“…Samples were countered in a double-blind manner. Data were expressed as percentage to saline-injected controls [ 26 , 39 ].…”

“…Real-time qPCR analysis was performed as described [26]. Briefly, total RNA was extracted with TRIzol and reverse transcribed to cDNA with TaKaRa RT kits (Dalian, China).…”

Measurable health effects associated with the daylight saving time shift

“…In a DST shift effect analysis, one should keep in mind that there are two distinct phenomena in play: (1) the natural variation of day length, the amount of light over the year, and the daily sunlight intensity cycle affects the human circadian clock, behavior, and numerous diseases [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45], and; (2) the disruption of individuals' daily schedule due to the DST shift. Our analyses were designed to target the effects associated with the latter, adjusting for the former with negative controls.…”