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Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-β (1–42) and NF-κB pathway

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Abstract

Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by a gradual decline in cognitive and memory functions of the aged peoples. Long-term exposure to heavy metals (aluminium and iron) cause neurotoxicity by amyloid plaques accumulation, tau phosphorylation, increased oxidative stress, neuroinflammation, and cholinergic neurons degeneration, contributes to the development of AD-like symptoms. The present research work is designed to investigate the neuroprotective effect of spermine in aluminium chloride (AlCl3), and iron (Fe) induced AD-like symptoms in rats. Rats were administered of AlCl3 (100 mg/kg p.o.) alone and in combination with iron (120 μg/g, p.o.) for 28 days. Spermine (5 and 10 mg/kg) through intraperitoneal (i.p.) route was given for 14 days. The recognition and spatial memory impairment were tasted using Morris water maze (MWM), actophotometer, and Novel Object Recognition test (NORT). All the rats were sacrificed on day 29, brains were isolated, and tissue homogenate was used for neuroinflammatory, biochemical, neurotransmitters, metals concentration, and nuclear factor-kappa B (NF-κB) analysis. In the present study, AlCl3 and iron administration elevated oxidative stress, cytokines release, dysbalanced neurotransmitters concentration, and biochemical changes. Rats treated with spermine dose-dependently improved the recognition and spatial memory, attenuated proinflammatory cytokine release, and restored neurotransmitters concentration and antioxidant enzymes. Spermine also mitigated the increased beta-amyloid (Aβ42), with downregulation of tau phosphorylation. Furthermore, spermine augmented the hippocampal levels of B cell leukaemia/lymphoma-2 (Bcl-2), diminished nuclear factor-kappa B (NF-κB) and caspase-3 (casp-3) expression. Moreover, spermine exhibited the neuroprotective effect through anti-inflammatory, antioxidant, neurotransmitters restoration, anti-apoptotic Aβ42 concentration.

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Abbreviations

AD:

Alzheimer’s disease

Al:

Aluminium

AlCl3:

Aluminium chloride

Fe:

Iron

MWM:

Morris water maze

SOD:

Superoxide dismutase

GR:

Glutathione reductase

IL:

Interleukin

NORT:

Novel object recognition test

LPO:

Lipid peroxidation

TNF-α:

Tumor necrosis factor-alpha

MDA:

Malondialdehyde

DA:

Dopamine

AChE:

Acetylcholinesterase

GABA:

Gamma-aminobutyric acid

Aβ:

Amyloid-β peptide

NFTs:

Neurofibrillary tangles

CNS:

Central nervous system

Ach:

Acetylcholine

ELISA:

Enzyme-linked immunosorbent assay

ECD:

Electrochemical detection

HPLC:

High-performance liquid chromatography

AAS:

Atomic absorption spectrophotometer

CPCSEA:

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

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Acknowledgements

All authors are thankful to Shri Praveen Garg, chairman ISF College of Pharmacy, Moga, Punjab for providing research platform.

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  1. Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India

    Khadga Raj & Shamsher Singh

  2. Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, 142001, India

    G. D. Gupta

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  1. Khadga Raj
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Raj, K., Gupta, G.D. & Singh, S. Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-β (1–42) and NF-κB pathway. Inflammopharmacol 29, 1777–1793 (2021). https://doi.org/10.1007/s10787-021-00883-y

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