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Pharmacological Modulation of TRPM2 Channels via PARP Pathway Leads to Neuroprotection in MPTP-induced Parkinson’s Disease in Sprague Dawley Rats

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Abstract

Transient receptor potential melastatin-2 (TRPM2) channels are cation channels activated by oxidative stress and ADP-ribose (ADPR). Role of TRPM2 channels has been postulated in several neurological disorders, but, it has not been explored in animal models of Parkinson’s disease (PD). Thus, the role of TRPM2 and its associated poly (ADPR) polymerase (PARP) signaling pathways were investigated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model using TRPM2 inhibitor, 2-aminoethyl diphenyl borinate (2-APB), and PARP inhibitor, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34). PD was induced by using a bilateral intranigral administration of MPTP in rats, and different parameters were evaluated. An increase in oxidative stress was observed, leading to locomotor and cognitive deficits in the PD rats. PD rats also showed an increased TRPM2 expression in the striatum and mid-brain accompanied by reduced expression of tyrosine hydroxylase (TH) in comparison to sham animals. Intraperitoneal administration of 2-APB and PJ-34 led to an improvement in the locomotor and cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and an increase in TH levels in the striatum and mid-brain. In addition, these pharmacological interventions also led to a decrease in the expression of TRPM2 in PD in the striatum and mid-brain. Our results provide a rationale for the development of potent pharmacological agents targeting the TRPM2-PARP pathway to provide therapeutic benefits for the treatment of neurological diseases like PD.

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Fig. 1
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taken from different gels and ACTIN, TH and TRPM2 exposures with their antibodies are different. Quantification for blots is shown in d TH in striatum, e TRPM2 in striatum, and f TRPM2 in mid-brain. Results were expressed as mean ± SEM. *p < 0.05 vs. sham animals; #p < 0.05, ##p < 0.01 vs. MPTP-induced PD animals (one-way ANOVA)

Fig. 7

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Data Availability

All data supporting the conclusions of this manuscript are provided in the text, figures and tables.

Abbreviations

TRPM2:

Transient receptor potential melastatin-2

ADPR:

Adenosine diphosphate ribose

PD:

Parkinson’s disease

PARP:

Poly (ADP-ribose) polymerase

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

2-APB:

2-Aminoethyl diphenyl borinate

PJ-34:

 N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride

TH:

Tyrosine hydroxylase

TRP:

Transient receptor potential

ROS:

Reactive oxygen species

NUDT9:

(Nucleoside diphosphate–linked moiety X)-type motif 9

PARG:

Poly (ADP-ribose) glycohydrolase

SNpc:

Substantia nigra pars compacta

AP:

Anteroposterior

ML:

Mediolateral

DV:

Dorsoventral

MDA:

Malondialdehyde

ANOVA:

One-way analysis of variance

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Funding

The present study was supported by financial support from start-up grant (R-12020/2017-HR) Department of Health Research, Ministry of Health and Family Welfare, Government of India. Also, authors received financial support from the National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India to carry out this work.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), 160062, Punjab, India

    Bhupesh Vaidya, Harpinder Kaur, Pavan Thapak, Shyam Sunder Sharma & Jitendra Narain Singh

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  1. Bhupesh Vaidya
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  2. Harpinder Kaur
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Contributions

BV: data curation; formal analysis; investigation; methodology; validation; visualization; writing—original draft; writing—review and editing. HK: investigation; data curation; formal analysis; methodology; visualization. PT: western bloting investigation and analysis; visualization. SSS: conceptualization; resources; supervision; writing—final review and editing. JNS: conceptualization; data curation; funding acquisition; project administration; resources; supervision; validation; visualization; roles/writing—original draft; review and editing.

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Correspondence to Jitendra Narain Singh.

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Research involving Human Participants and/or Animals

Experiments were carried out in accordance with the Committee for the Purpose of Control and Supervision on Experiments on Animals, Government of India; and after approval of Institutional Animal Ethics Committee of National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab, India (IAEC/18/19 and IAEC/ 17/25).

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Supplementary file1 Supplementary Fig 1: Fura-2AM assay for the measurement of intracellular calcium influx to study the effect of 2-APB on calcium influx on SH-SY5Y cells. (JPG 2433 KB)

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Supplementary file2 Supplementary Fig 2: GSH estimation carried out in the (A) Mid-Brain (B) Hippocampus (C) Striatum (D) Cortex. (JPG 3172 KB)

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Vaidya, B., Kaur, H., Thapak, P. et al. Pharmacological Modulation of TRPM2 Channels via PARP Pathway Leads to Neuroprotection in MPTP-induced Parkinson’s Disease in Sprague Dawley Rats. Mol Neurobiol 59, 1528–1542 (2022). https://doi.org/10.1007/s12035-021-02711-4

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