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Acute Hypobaric Hypoxia Exposure Causes Neurobehavioral Impairments in Rats: Role of Brain Catecholamines and Tetrahydrobiopterin Alterations

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Abstract

Hypoxia is a state in which the body or a specific part of the body is deprived of adequate oxygen supply at the tissue level. Sojourners involved in different activities at high altitudes (> 2500 m) face hypobaric hypoxia (HH) due to low oxygen in the atmosphere. HH is an example of generalized hypoxia, where the homeostasis of the entire body of an organism is affected and results in neurochemical changes. It is known that lower O2 levels affect catecholamines (CA), severely impairing cognitive and locomotor behavior. However, there is less evidence on the effect of HH-mediated alteration in brain Tetrahydrobiopterin (BH4) levels and its role in neurobehavioral impairments. Hence, this study aimed to shed light on the effect of acute HH on CA and BH4 levels with its neurobehavioral impact on Wistar rat models. After HH exposure, significant alteration of the CA levels in the discrete brain regions, viz., frontal cortex, hippocampus, midbrain, and cerebellum was observed. HH exposure significantly reduced spontaneous motor activity, motor coordination, and spatial memory. The present study suggests that the HH-induced behavioral changes might be related to the alteration of the expression pattern of CA and BH4-related genes and proteins in different rat brain regions. Overall, this study provides novel insights into the role of BH4 and CA in HH-induced neurobehavioral impairments.

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Data availability

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Abbreviations

BH4:

Tetrahydrobiopterin

CA:

Catecholamine

CNS:

Central nervous system

COMT:

Catechol-O-methyltransferase

DA:

Dopamine

DAPI:

4′,6-Diamidino-2-phenylindole

DBH:

Dopamine-β-hydroxylase

DDC:

Aromatic l-amino acid decarboxylase

DHFR:

Dihydrofolate reductase

DTT:

Dithiothreitol

GCH1:

GTP cyclohydrolase 1

GTP:

Guanosine-5'-triphosphate

HH:

Hypobaric hypoxia

HIF-1α:

Hypoxia-inducible factor 1-alpha

HPLC:

High-performance liquid chromatography

HRP:

Horseradish peroxidase

MAO:

Monoamine oxidase

NE:

Norepinephrine

NO:

Nitric oxide

O2 :

Oxygen

PD:

Parkinson’s disease

PCBD1:

Pterin-4a-carbinolamine dehydratase 1

PNMT:

Phenylethanolamine N-methyltransferase

PTPS:

6-Pyruvoyltetrahydropterin synthase

PVDF:

Polyvinylidene fluoride

QDPR:

Quinoid dihydropteridine reductase

SMA:

Spontaneous motor activity

SPR:

Sepiapterin reductase

TH:

Tyrosine hydroxylase

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Acknowledgements

We thank Dr. K. Kadirvelu, Director, DRDO-BU CLS and Dr. T. Anand, HOD NBT Division, DFRL, Mysore, for their support. The authors would like to acknowledge DST-SERB (EMR/2014/000600) for the vibratome facility. The authors would also like to thank Dr. K. Maharajan, Dr. M. Venkataramana, Dr. S. Thenmozhi, Dr. G. Vimal, Mr. K. V. Vignesh, Mr. M. Naika, Mr. S. Teja, Ms. U. Sathisaran, Ms. M. Tomy, Ms. A. Roonie, and Mr. D. Bhattacharjee for their valuable inputs. Authors would specially like to thank Mr. Sujoy Dey (Leica Microsystems, Bengaluru) for facilitating confocal microscopy imaging at Aravind Medical Research Foundation, Madurai, Tamil Nadu, India.

Funding

This work was supported by DRDO-BU Centre for Life Sciences and funded by the Ministry of Defence, New Delhi, India for financial support (DLS/86/50011/DRDO-BU Centre/Phase-II/2014).

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Authors and Affiliations

  1. DRDO-BU Centre for Life Sciences, Bharathiar University, Coimbatore, 641 046, India

    Monojit Bhattacharjee & Ekambaram Perumal

  2. Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, 641 046, India

    Suryaa Manoharan & Ekambaram Perumal

  3. Nutrition, Biochemistry & Toxicology Division, Defence Food Research Laboratory, Mysore, 570 011, India

    Uma Maheswari Deshetty

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  1. Monojit Bhattacharjee
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Contributions

Funding acquisition and Supervision: EP; Conceptualization: MB and EP; Methodology: MB, SM and UMD; Formal analysis and investigation: EP and SM; Writing—original draft preparation: MB; Writing—review and editing: EP and SM; Resources: EP.

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Correspondence to Ekambaram Perumal.

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All procedures followed the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and animal ethical committee of Bharathiar University (Approval No: 722/Go/Re/S/02/CPCSEA), Coimbatore, India.

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Bhattacharjee, M., Manoharan, S., Deshetty, U.M. et al. Acute Hypobaric Hypoxia Exposure Causes Neurobehavioral Impairments in Rats: Role of Brain Catecholamines and Tetrahydrobiopterin Alterations. Neurochem Res 48, 471–486 (2023). https://doi.org/10.1007/s11064-022-03767-x

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