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Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats

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Abstract

Striatal neurotoxicity is the pathological hallmark for a heterogeneous group of movement disorders like Tardive dyskinesia (TD) and Huntington’s disease (HD). Both diseases are characterized by progressive impairment in motor function. TD and HD share common features at both cellular and subcellular levels. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor (GCSF), shows neuroprotective properties in in-vivo models of movement disorders. This study seeks to evaluate the neuroprotective effect of filgrastim in haloperidol and 3-NP-induced neurotoxicity in rats. The study was divided into two: in study one, rats were administered with haloperidol for 21 days, filgrastim at the dose of (20, 40, 60 µg/kg,s.c.) was administered once a day before haloperidol treatment and the following parameters (orofacial movements, rotarod, actophotometer) were performed to assess TD. Similarly, in the second study, rats were administered with 3-NP for 21 days, filgrastim at a dose of (20 and 40 µg/kg, s.c.) was administered, and the following parameters (rotarod, narrow beam walk, and open field test) were assessed for HD. On the 22nd day, animals were sacrificed and cortex and striatum isolated for oxidative stress (LPO, GSH, SOD, catalase, and nitrate) marker assessment. Results revealed that haloperidol and 3-NP treatment significantly impaired motor coordination, and oxidative defense inducing TD and HD-like symptoms. Treatment with filgrastim significantly averted haloperidol and 3-NP-induced behavioral and biochemical alterations. Conclusively, the neuroprotective effect of filgrastim is credited to its antioxidant properties. Hence, filgrastim might be a novel therapeutic candidate for the management of TD and HD.

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Abbreviations

3-NP:

3-Nitropropionic acid

AD :

Alzheimer’s disease

ATP:

Adenosine triphosphate

BBB:

Blood-brain barrier

bcl-2:

B-cell lymphoma 2

BDNF:

Brain-derived neurotrophic factor

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

CPCSEA:

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

EPO:

Erythropoietin

ERK:

Extracellular regulated kinase

ETC:

Electron transport chain

FGF:

Fibroblast growth factors

FG:

Filgrastim

FJ:

Facial jerking

GABA:

Gamma aminobutyric acid

GCSF:

Granulocyte colony-stimulating factor

GPe:

Globus pallidus externa

GPi:

Globus pallidus interna

GSH:

Reduced glutathione

HD:

Huntington’s disease

HP:

Haloperidol

HTT:

HTT protein

IAEC:

Institutional Animal Ethics Committee

LPO :

Lipid peroxidation

MDA:

Malondialdehyde

mHTT:

Mutant HTT protein

MSN:

Medium spiny neurons

NMDA:

N-Methyl-D-aspartic acid or N-Methyl-D-aspartate

NO:

Nitric oxide

NR2β:

N-methyl D-aspartate receptor subtype 2β

OFT:

Open field test

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SD:

Sprague Dawley

SNpr:

Substantia nigra pars reticulata

SOD:

Superoxide dismutase

STAT:

Signal transducer and activator of transcription

STN:

Subthalamic nucleus

TD:

Tardive dyskinesia

TP:

Tongue protrusions

VCM:

Vacuous chewing movements

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India

    Vikrant Rahi & Parladh Ram

  2. Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India

    Puneet Kumar

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  1. Vikrant Rahi
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  2. Parladh Ram
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Contributions

PK conceived and designed the research. VR conducted the experiment on 3-NP-induced Huntington’s-like symptoms and PR conducted the experiment on haloperidol-induced Tardive dyskinesia and PK, VR, and PR wrote the manuscript. All authors read and approve the manuscript, and all data were generated in-house and that no paper mill was used.

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Correspondence to Puneet Kumar.

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Ethical Approval for study 1—MRSPTU/IAEC/2018/010.

Ethical Approval for study 2—MRSPTU/IAEC/2019/09.

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Rahi, V., Ram, P. & Kumar, P. Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats. Neurotox Res 40, 2089–2102 (2022). https://doi.org/10.1007/s12640-022-00604-5

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