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Intranasal Rotenone Induces Alpha-Synuclein Accumulation, Neuroinflammation and Dopaminergic Neurodegeneration in Middle-Aged Mice

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Abstract

Accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson’s disease (PD). Previous studies suggest that α-syn pathology may originate from the olfactory bulb (OB) or gut in response to an unknown pathogen and later progress to the different brain regions. Aging is viewed as the utmost threat to PD development. Therefore, studies depicting the role of age in α-syn accumulation and its progression in PD are important. In the present study, we gave intranasal rotenone microemulsion for 6 weeks in 12-month-old female BALB/c mice and found olfactory dysfunction after 4 and 6 weeks of rotenone administration. Interestingly, motor impairment was observed only after 6 weeks. The animals were sacrificed after 6 weeks to perform western blotting and immunohistochemical studies to detect α-syn pathology, neuroinflammation and neurodegeneration. We found α-syn accumulation in OB, striatum, substantia nigra (SN) and cortex. Importantly, we found significant glial cell activation and neurodegeneration in all the analysed regions which were absent in our previous published studies with 3 months old mice even after they were exposed to rotenone for 9 weeks indicating age is a crucial factor for α-syn induced neuroinflammation and neurodegeneration. We also observed increased iron accumulation in SN of rotenone-exposed aged mice. Moreover, inflammaging was observed in OB and striatum of 12-month-old BALB/c mice as compared to 3-month-old BALB/c mice. In conclusion, there is a difference in sensitivity between adult and aged mice in the development and progression of α-syn pathology and subsequent neurodegeneration, for which inflammaging might be the crucial probable mechanism.

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Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

Abbreviations

α-syn:

Alpha-synuclein

BCA:

Bicinchoninic acid

CPCSEA:

Committee for the Purpose of Control and Supervision of Experiments on animals

DAB:

3,3′-Diaminobenzidine

DA:

Dopamine

DAergic:

Dopaminergic

DPX:

Dibutylphthalate Polystyrene Xylene

CNS:

Central nervous system

GFAP:

Glial fibrillary acidic protein

IAEC:

Institutional animal ethics committee

Iba-1:

Ionized calcium binding adaptor molecule 1

IHC:

Immunohistochemistry

i.n:

Intranasal

mAb:

Monoclonal antibody

ME:

Microemulsion

NFkB:

Nuclear Factor Kappa B

OB:

Olfactory bulb

pAb:

Polyclonal antibody

PBS:

Phosphate buffer saline

PD:

Parkinson’s disease

PFA:

Paraformaldehyde

PMSF:

Phenylmethyl sulfonyl fluoride

pTH:

Phosphorylated tyrosine hydroxylase

psyn:

Phosphorylated alpha-synuclein

PVDF:

Polyvinylidene fluoride

RIPA buffer:

Radioimmunoprecipitation assay buffer

RBWT:

Round beam walk test

SDS:

Sodium dodecyl sulphate

SLS:

Sodium lauryl sulphate

SN:

Substantia nigra

SNc:

Substantia nigra pars compacta

TEMED:

Tetramethyl-ethylenediamine

TH:

Tyrosine hydroxylase

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Acknowledgements

The authors acknowledge National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad administration for providing the facility and support for conducting this study. They are supported by project no. LX22NPO5107 (MEYS): financed by European Union – Next Generation EU.

Funding

This supplement was supported by the National Institute of Pharmaceutical Education and Research (NIPER) seed fund-Ahmedabad, Department of Pharmaceutics, Ministry of Chemicals and Fertilizers, Government of India. Dr. Amit Khairnar gratefully acknowledges the support of the Ramalingaswami Fellowship (No. BT/RLF/Re-entry/24/2017) from the Department of Biotechnology, India.

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  1. Amit Khairnar

    Present address: International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic, ICRC, FNUSA, Brno, Czech Republic

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Palaj, Ahmedabad, Gandhinagar, 382355, Gujarat, India

    Monika Sharma, Nishant Sharma & Amit Khairnar

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Contributions

Conception and study design was done by AK and MS. Data acquisition was done by MS and NS. Data was analysed by MS and NS. Manuscript was written by MS and revised by AK, MS and NS.

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Correspondence to Amit Khairnar.

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No clinical study was conducted. Experimental design for pre-clinical study was approved by IAEC Committee of NIPER Ahmedabad (IAEC approval number: NIPERA/IAEC/2019/19). All efforts were made to minimize animal suffering and to reduce the number of animals used.

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Sharma, M., Sharma, N. & Khairnar, A. Intranasal Rotenone Induces Alpha-Synuclein Accumulation, Neuroinflammation and Dopaminergic Neurodegeneration in Middle-Aged Mice. Neurochem Res 48, 1543–1560 (2023). https://doi.org/10.1007/s11064-022-03847-y

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