Parkinsonian Rotenone Mouse Model: Reevaluation of Long-Term Administration of Rotenone in C57BL/6 Mice

Abstract

Chronic systemic exposure of Lewis rats to rotenone produced many features of Parkinson's disease (PD), including nigrostriatal dopamine (DA) neurodegeneration and the formation of cytoplasmic inclusions in nigral DA neurons. We also reported that chronic oral administration of rotenone at 30 mg/kg for 28 d caused specific nigrostriatal DA neurodegeneration in C57BL/6 mice. To establish a PD model more suitable for evaluating nigrostriatal DA neurodegeneration, the present study has been designed to assess the neurotoxicity of rotenone after daily oral administration at 30 or 100 mg/kg for 56 d in C57BL/6 mice. The survival rate of rotenone-treated mice at 30 mg/kg did not change from 28 to 56 d, although the survival rate of rotenone-treated mice at 30 mg/kg was decreased to about 70% within one week. The survival rate of the rotenone-treated mice at 100 mg/kg was suddenly decreased after 28 d, and finally to about 15% at 56 d. Rotenone at 30 mg/kg, but not 100 mg/kg, for 28 d caused a significant loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. Rotenone at 100 mg/kg caused a highly variable loss of TH-positive neurons among individual mice. Rotenone at 30 mg/kg for 56 d caused a significant loss of TH-positive neurons and behavioral impairment. In addition, α-synuclein immunoreactivity was increased in surviving TH-positive neurons in a time-dependent manner. Thus, this protocol for chronic administration of rotenone at 30 mg/kg for 56 d is more useful for understanding the mechanism of DA neurodegeneration.

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

“…Inden and colleagues showed that chronic oral administration of rotenone at 30 mg/kg for 56 days in C57BL/6 mice caused a significant and selective loss of nigral DA neurons and induced behavioral impairment. In addition, a-synuclein immunoreactive cytoplasmic inclusions similar to Lewy bodies were observed in surviving DA neurons in a time-dependent manner (47). This recently optimized mouse rotenone model may thus provide a powerful model system in which to study gene-environment interactions if the chronic rotenone regimen is used in mice that are transgenic for genes linked to human PD.…”

Protection Against Dopaminergic Neurodegeneration in Parkinson’s Disease–Model Animals by a Modulator of the Oxidized Form of DJ-1, a Wild-type of Familial Parkinson’s Disease–Linked PARK7

“…However, a major advantage of the 6-OHDA model is that it gives a quantifiable motor deficit (rotation) (37). On the other hand, we reported that chronic oral administration of rotenone caused specific nigrostriatal DA neurodegeneration in C57BL/6 mice (38,39). In rotenone-treated mice, α-synuclein immunoreactivity was increased in some surviving tyrosine hydroxylase (TH)-positive neurons in the substantia nigra.…”

“…The number of α-synuclein and TH double-positive neurons increased in a time-dependent manner. The previous experimental condition in the rotenone model may resemble early PD symptoms rather than atypical parkinsonism, although long-term treatment with rotenone is necessary (38,39). Therefore, in the present study, we used 6-OHDA-microinjected rats and rotenone-treated mice as acute and chronic animal models of PD, respectively.…”

The Effect of Treadmill Exercise on Expression of α-synuclein and miRNA in MPTP Induced-mouse Models of Parkinson’s Disease

“…In animals, rotenone has been administered by different routes. Oral administration appears to cause little neurotoxicity [84,85]. Chronic systemic administration using osmotic pumps has been the most common delivery regimen, especially in the Lewis rat, which may be more sensitive to rotenone than other strains of rats [86].…”

“…Attempts to lesion other animal species such as mice or monkeys have not been successful at all [72,92]. However, recent studies by two groups have demonstrated that oral administration of rotenone to mice causes nigral degeneration, a decrease of striatal dopamine levels, and motor dysfunction [85,93,94]. They also demonstrated α-synuclein aggregation in different areas of the brain [95].…”