Elsevier

Life Sciences

Volume 288, 1 January 2022, 120186
Life Sciences

Review
Neuropeptides: Potential neuroprotective agents in ischemic injury

https://doi.org/10.1016/j.lfs.2021.120186Get rights and content

Highlights

  • Neuropeptides are critical for controlling the brain's response to various inputs and conditions, including ischemia

  • Neuropeptides are an element of the natural defense system in ischemic injury

  • Neuropeptides act as a neuroprotective agents in ischemic injury.

  • Neuropeptides play a critical part in the brain's self-preservation and recovery following ischemia

  • Neuropeptides such as PACAP, CGRP, and NPY show their neuroprotective effects by reducing apoptosis

Abstract

Aim

Ischemic damage to the brain is linked to an increased rate of morbidity and mortality worldwide. In certain parts of the world, it remains a leading cause of mortality and the primary cause of long-term impairment. Ischemic injury is exacerbated when particular neuropeptides are removed, or their function in the brain is blocked, whereas supplying such neuropeptides lowers ischemic harm. Here, we have discussed the role of neuropeptides in ischemic injury.

Materials & methods

Numerous neuropeptides had their overexpression following cerebral ischemia. Neuropeptides such as NPY, CGRP, CART, SP, BK, PACAP, oxytocin, nociception, neurotensin and opioid peptides act as transmitters, documented in several “in vivo” and “in vitro” studies. Neuropeptides provide neuroprotection by activating the survival pathways or inhibiting the death pathways, i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB.

Key findings

Neuropeptides have numerous beneficial effects in ischemic models, including antiapoptotic, anti-inflammatory, and antioxidant actions that provide a powerful protective impact in neurons when combined. These innovative therapeutic substances have the potential to treat ischemia injury due to their pleiotropic modes of action.

Significance

This review emphasizes the neuroprotective role of neuropeptides in ischemic injury via modulation of various signalling pathways i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB.

Introduction

Any tissue can experience decreased arterial flow due to vascular constriction, blockage, or a substantial drop in perfusion pressure. The effects are more pronounced in highly differentiated tissues, such as the heart, kidney, and brain. These tissues, in general, require a high concentration of oxygen to give the energy necessary to perform their numerous specialized functions [1]. Central nervous system (CNS) injuries initiate a complex cascade of secondary biochemical and molecular reactions that aggravate the initial primary injury and associated neurological impairments [2], [3]. Numerous variables have been implicated in the secondary phase of injury, including blood-brain barrier (BBB) disruption, edema development, neurotoxic excitatory amino acid release, oxidative stress, and apoptosis. Neuroprotection is a notion that is based on the development of appropriate pharmacological therapies that inhibit these secondary processes and improve patients' functional outcomes [4]. Neuropeptides are critical for controlling the brain's response to various inputs and conditions, including ischemia [5]. Following cerebral ischemia, various endogenous neuropeptides exhibit increased expression to protect the neurons via modulating different processes, i.e., excitotoxicity, oxidative stress, apoptosis, and inflammation. Some endogenous neuropeptides also manifest neuroprotection by either enhancing cerebral blood flow or promoting neurogenesis [6]. Ischemia injury is exacerbated by inhibiting or blocking particular neuropeptides in the brain, whereas delivering these neuropeptides alleviates ischemic injury in rats. Thus, an increase in the expression of specific neuropeptides to the ischemic stress is a defensive mechanism of the brain [7]. Neuropeptides play a critical part in the brain's self-preservation and recovery following ischemia [8]. Notably, numerous experimental stroke studies have demonstrated altered activity and expression of brain peptidases and related neuropeptide systems and have established a relationship between their function and stroke pathology. Numerous neuropeptide systems have been recognized as optimistic targets for neuroprotective and neurodegenerative therapies [9], [10]. This review focuses on the critical role of neuropeptides as neuroprotective agents following ischemia injury.

A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the help of the keywords like “Neuropeptides; Cerebral ischemia; Neuroprotection; Apoptosis; Inflammation” till August 2021. The review was conducted using the above keywords to collect the latest articles and understand the nature of the extensive work done on the modulation neuropeptides: Potential neuroprotective agents in ischemic injury.

Section snippets

Pathophysiology of ischaemic injury

Ischemia is a condition in which the blood vessels become clogged, resulting in a cessation or reduction of blood flow. The affected area receives an insufficient supply of oxygen and glucose. Ischemia causes tissue damage through a mechanism called the ischemic cascade. The damage is caused by the accumulation of metabolic waste, mitochondrial damage, the inability of the cells to maintain their membranes, and eventually the release of autolyzing proteolytic enzymes into the tissues

Neuropeptides and their receptors

A neuropeptide may be defined as a small substance made of proteins that are synthesized by neurons and secreted in a controlled manner to work on neural substrates such as glial cells and neurons and non-neuronal target cells such as glands and muscles. Neuropeptides are peptides that neurons employ to communicate with other cells. As neuropeptides are generated and functional in the neurological system, they would include chemokines of the immune system, peptide hormones of the endocrine

Neuropeptides as neuroprotective agent in ischemic injury

Peptides are chemical compounds composed of covalently linked amino acid monomers. The smallest are dipeptides, composed of two amino acids linked together by a single amide bond, preceded by tripeptides, tetrapeptides, etc. [32]. Neuropeptides are found in and released from a diverse selection of nerves. They are chemically different and exhibit distinctive localization patterns throughout the CNS and PNS, stimulating a vast range of biological functions. Burnstock (1976) pioneered the notion

MAPK signalling pathway

A cascade of mitogen-activated protein kinase (MAPK) is crucial in translating extracellular signals into cellular responses. Three MAPK families have been identified in mammalian cells: classical MAPK (also called ERK), C-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 kinase [140]. Numerous proteins are involved in the pathway, including MAPK, formerly named ERK (extracellular signal-regulated kinases), which interact by attaching phosphate groups to a nearby protein

Clinical trials (Table 2)

There is not much availability of clinical data showing the neuroprotective potential of neuropeptides in ischemic injury. The following table summarizes some of the studies involving neuropeptides in cerebral ischemia.

Conclusion and future perspectives

Given the rapid development of new therapeutic methods, ischemia management all too frequently produces unsatisfactory results. Ischemia is mainly caused by cell death as a pathogenic mechanism. The study of neuropeptide systems in ischemia injury forms a framework for utilizing peptidergic receptors as a possible target for brain damage. Additionally, the body of evidence supporting the therapeutic potential of agonists at numerous peptide receptors discussed in this study continues to grow.

CRediT authorship contribution statement

Conceptualization: Conceived- and designed the experiments: Thakur Gurjeet Singh. Analyzed the data: Amarjot Kaur. Wrote the manuscript: Priyanka Saklani, Heena Khan. Visualization: Saurabh Gupta, Amarjot Kaur Editing of the Manuscript: Heena khan, Amarjot Kaur, Thakur Gurjeet Singh Critically reviewed the article: Thakur Gurjeet Singh Supervision: Thakur Gurjeet Singh.

All authors read and approved the final manuscript.

Declaration of competing interest

There are no conflicts of interest.

Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for providing the necessary facilities to carry out the research work.

Ethics approval and consent to participate

Not applicable.

Funding

Nil.

Availability of data and material

Not applicable.

Compliance with ethical standards

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

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