Intranasal Exposure to Low-Dose Rotenone Induced Alpha-Synuclein Accumulation and Parkinson's Like Symptoms Without Loss of Dopaminergic Neurons

Epidemiologically Parkinson's disease (PD) is associated with chronic ingestion or inhalation of environmental toxins leading to the development of motor symptoms. Though neurotoxin-based animal models played a major role in understanding diverse pathogenesis, they failed to identify the risk assessment due to uncommon route of toxin exposure. Towards this, the available neurotoxin-based intranasal (i.n.) PD models targeting olfactory bulb (OB) have demonstrated the dopaminergic (DAergic) neurodegeneration in both OB and substantia nigra (SN). Despite that, the studies detecting the alpha-synuclein (alpha-syn) accumulation in OB and its progression to other brain regions due to inhalation of environmental toxins are still lacking. Herein, we developed oil in water microemulsion of rotenone administered intranasally to the mice at a dose which is not detectable in blood, brain, and olfactory bulb by LCMS method. Our data reveals that 9 weeks of rotenone exposure did not induce olfactory and motor dysfunction. Conversely, after 16 weeks of washout period, rotenone treated mice showed both olfactory and motor impairment, along with alpha-syn accumulation in the OB and striatum without glial cell activation and loss of dopaminergic neurons. The results depict the progressive nature of the developed model and highlight the role of alpha-syn in PD like pathology or symptoms. Together, our findings suggest the adverse consequences of early exposure to the environmental toxins on the olfactory system for a shorter period with relevance to the development of synucleinopathy or Parkinson's disease in its later stage.

Automated summary

This study established a PD model administered intranasally with rotenone, showing that long-term exposure to rotenone can lead to motor and olfactory dysfunction, along with the accumulation of alpha-syn in the olfactory bulb and striatum. The model demonstrates the progressive nature of the disease and highlights the role of alpha-syn in PD pathology or symptoms.