Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches

https://doi.org/10.1016/j.intimp.2022.108902Get rights and content

Highlights

  • Traumatic brain injury (TBI) happens due to motor vehicle accidents, the building falls, and injuries.

  • Neuroinflammation is caused by TBI and can aggravate the progression of tissue deterioration.

  • TBI increase the production of brain-derived neurotrophic factors.

  • TBI pathogenesis is associated with NOX, a class of enzymes whose sole function is to generate ROS.

Abstract

TBI has been one of the top causes of death and morbidity worldwide, yet despite enormous efforts to discover neuroprotective therapeutics for this serious disease, no beneficial outcomes in human clinical trials have been reported to date. Traumatic brain injury (TBI) can occur as a result of any type of trauma, from a simple hit to the head to a penetrating injury to the brain. TBI causes delayed secondary damage events as a result of neurochemical, metabolic, and cellular alterations that account for many of the neurological impairments reported following TBI. We focus on the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration in our discussion, which is structured around the kinetics of the immune response to TBI — from immediate triggers through chronic neuroinflammation. Neuroinflammation is caused by traumatic brain injury and can aggravate the progression of tissue deterioration. Immune cells respond acutely to signals from injured cells, develop neuroinflammation, and eventually cause pathology. So neuroinflammation and the immune system could be a target for TBI treatment. However, there are various approaches to the treatment of TBI. This review will provide the literature-based modulation of receptors, ion channels, transporters, and enzymes to attenuate traumatic brain injury.

Introduction

The neuroinflammation response to Traumatic brain injury (TBI) includes the activation of glia, the production of inflammatory mediators within the brain, and the migration of peripheral immune cells. Multiple neuroinflammation markers have been discovered in both animal models of TBI and human patients, and they appear to be linked to both patient and animal model outcome metrics [1]. Understanding the cellular and molecular mechanisms that drive neuroinflammation by combining the approaches discussed in the review may aid in developing new therapeutics aimed at controlling the inflammatory response acutely post-injury to reduce the short and long-term effects of TBI [2]. According to the study, after the current mechanical injury in TBI, there may be a delayed secondary injury and a variety of neuroinflammatory events. Several signaling molecules and metabolic abnormalities cross the blood-brain barrier hours to days following a TBI, resulting in immune cell extravasation and cerebral edema [1]. The primary, immediate harm in TBI is caused by impact and cannot be cured; however, the timeframe and pathophysiology of the delayed, secondary injury provide a window of therapeutic possibilities [3]. A mathematical modeling framework, a novel approach in TBI, demonstrates the ability to computationally extract intervention target estimates based on a mechanistic understanding of the underlying physiology [4]. This mathematical modeling framework can be used in future studies as a manipulable system to simulate pharmacological intervention effects and improve our understanding of neuroinflammatory kinetics by adjusting target parameters that are mechanistically important to the neuroinflammatory system [4]. Following TBI, several studies predicted that early stratification of various patient subdivisions based on neuroinflammatory differences could support individualized therapies that modulate the microglial response, such as the balance and timing of transitions between M1- and M2-like states or inflammation-related procedures [5]. New evidence on phenotypic markers and specific roles of each microglia subtype and validating model predictions with additional patient data will aid in developing TBI interferences that harness the multifaceted nature of neuroinflammation and microglia to mitigate secondary injury and improve patient outcomes [5], [6]. TBI activates the NLRP3 inflammasome early after injury, which plays a crucial role in propagating neuroinflammatory cascades in the brain, increasing secondary tissue damage [1]. Recently, a novel tiny molecule inhibitor of NLRP3 activation was discovered. This is the first study to show that a new NLRP3 inhibitor, which targets the NLRP3 inflammasome-triggered neuroinflammatory response, is neuroprotective for the injured brain during the acute stage after a TBI. More research into the effectiveness of new inhibitors throughout the chronic stage of TBI will aid in its development and translational potential [6].

A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the help of the keywords like “ Traumatic Brain Injury; Neuroinflammation; Glial cells; Oxidative Stress; Inflammatory mediators; Neurodegeneration” till 2022. The review was conducted using the above keywords to collect the latest articles and understand the nature of the extensive work done on the role of neuroinflammation and its inhibition in Traumatic Brain Injury.

Section snippets

Neuroprotective strategy in TBI

Due to the sheer ongoing quest for a thorough knowledge of TBI, there are still disputes over whether any model could accurately duplicate the intricate process in vivo. Mechanical injuries to tissue, cell membranes, and the blood–brain barrier are the most common TBI injuries [7]. TBI is a complex condition that includes extrinsic compression from a mass lesion, concussion, diffuse axonal injury, and several pathological mechanisms that can cause neuronal injuries, such as ischemia, apoptosis,

Vascular event

In those who have suffered a moderate or severe TBI, hemorrhage is a common symptom of acute vascular dysfunction. Changes in the BBB and cerebral blood vessels are frequently accompanied by the development of edema, which has severe morbidity and mortality implications because it causes intracranial hypertension and contributes to the vicious cycle of the secondary damage cascade [61]. A significant contributor is a vasogenic edema caused by BBB breakdown and hyperpermeability. When the BBB is

Histamine

Histamine is a neurotransmitter and neuromodulator in the central nervous system. Histaminergic neurons' cell bodies are only found in the hypothalamic tuberomammillary nuclei [69]. Mast cells in the meninges are critical effector cells in the immune system of stroke; this is because all blood vessels pass through the meninges before accessing the brain [70]. Mast cells are long-term resident immune cells in the meninges that store preformed and activated mediators in electron-dense cytoplasmic

Receptors and transducer mechanisms

SHT11 are cavity-induced allosteric modifiers that bind to the TNF receptor and prevent downstream signaling because neuroinflammation and TNF signaling are pathophysiological features of clinical TBI [99]. SGT11 significantly reduced cortical inflammatory cytokines three hours after a TBI. SGT11 aided in the recovery of cognitive, sensorimotor, and neurological abilities. These findings support that reducing TNFR-induced NF-ƙB signaling improves functional outcomes following brain damage [100]

Clinical trial

The currently available trial registries include information about trials that are now underway or have just concluded. The unsatisfactory clinical studies may be related to treatment strategy variety and the heterogeneity of the TBI patient population, a race against time to mitigate inevitable cell death. We offer a summarized clinical study with respect to neuroinflammation to guide future preclinical and clinical experiments designed to optimize the inflammatory responses to TBI.

Conclusion and future perspective

TBI is the most widespread disease globally and can have considerable fatal implications in newborns, adolescents, and elderly animals due to developmental or senescent brain features. Nonetheless, few preclinical research has been conducted to date on posttraumatic neuroinflammation and its implications in mice. Neuroinflammation represents a promising intervention option for TBI, as it can be both harmful and beneficial to the recovering brain. The review summarizes the correlation between

Ethics approval and consent to participate:

Not applicable.

Consent for Publication

All authors read and given their consent for the final manuscript.

Availability of data and materials

Not applicable.

Funding

Nil.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

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.

References (154)

  • Y. Akamatsu et al.

    Cell Death and Recovery in Traumatic Brain Injury

    Neurotherap.: J. Am. Soc. Exp. NeuroTherapeut.

    (2020)
  • S. Marjani et al.

    Doxycycline alleviates acute traumatic brain injury by suppressing neuroinflammation and apoptosis in a mouse model

    J. Neuroimmunol.

    (2021)
  • E. Saglam et al.

    Papaverine provides neuroprotection by suppressing neuroinflammation and apoptosis in the traumatic brain injury via RAGE- NF-B pathway

    J. Neuroimmunol.

    (2021)
  • K. Thapa et al.

    Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases

    Life Sci.

    (2021)
  • T.W. Lai et al.

    Excitotoxicity and stroke: identifying novel targets for neuroprotection

    Prog. Neurobiol.

    (2014)
  • A.A. Ladak et al.

    A Review of the Molecular Mechanisms of Traumatic Brain Injury

    World Neurosurg.

    (2019)
  • A.R. Nelson et al.

    Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

    BBA

    (2016)
  • R. Liao et al.

    Histamine H1 Receptors in Neural Stem Cells Are Required for the Promotion of Neurogenesis Conferred by H3 Receptor Antagonism following Traumatic Brain Injury

    Stem Cell Rep.

    (2019)
  • N. Liu et al.

    Downregulation of lncRNA KCNQ1OT1 relieves traumatic brain injury induced neurological deficits via promoting “M2” microglia polarization

    Brain Res. Bull.

    (2021)
  • L. Wang et al.

    Neuroprotective effects of epoxyeicosatrienoic acids

    Prostaglandins Other Lipid Mediat.

    (2018)
  • J.W. Phillis et al.

    Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders

    Brain Res. Rev.

    (2006)
  • K. Thapa et al.

    Traumatic brain injury: mechanistic insight on pathophysiology and potential therapeutic targets

    J. Mol. Neurosci.

    (2021)
  • F. Sivandzade et al.

    Traumatic Brain Injury and Blood-Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

    Int. J. Mol. Sci.

    (2020)
  • L.E. Vaughan et al.

    A mathematical model of neuroinflammation in severe clinical traumatic brain injury

    J. Neuroinflamm.

    (2018)
  • G. Tarantino et al.

    Could SCGF-beta levels be associated with inflammation markers and insulin resistance in male patients suffering from obesity-related NAFLD?

    Diagnostics

    (2020)
  • R. Kuwar et al.

    A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury

    J. Neuroinflamm.

    (2019)
  • M. Shafiei et al.

    A Comprehensive Review on the Applications of Exosomes and Liposomes in Regenerative Medicine and Tissue Engineering

    Polymers

    (2021)
  • Y. Jia et al.

    Niche Cells Crosstalk In Neuroinflammation After Traumatic Brain Injury

    Int. J. Biol. Sci.

    (2021)
  • H. Khan, A.K. Grewal, T.G. Singh, Pharmacological postconditioning by protocatechuic acid attenuates brain injury in...
  • J. Weiland et al.

    Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH)

    Int. J. Mol. Sci.

    (2021)
  • S.U. Rehman et al.

    Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK/CREB Signaling

    Cells

    (2019)
  • H. Khan et al.

    Pharmacological postconditioning: a molecular aspect in ischemic injury

    J. Pharm. Pharmacol.

    (2020)
  • Y.Z. Ren et al.

    Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria

    J. Neurochem.

    (2020)
  • M.T. Islam

    Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

    Neurol. Res.

    (2017)
  • O. BenAri et al.

    A double-blind placebo-controlled clinical trial testing the effect of hyperbaric oxygen therapy on brain and cognitive outcomes of mildly cognitively impaired elderly with type 2 diabetes: Study design

    Alzheimer's & dementia (New York N. Y.)

    (2020)
  • B. Li et al.

    Miro1 Regulates Neuronal Mitochondrial Transport and Distribution to Alleviate Neuronal Damage in Secondary Brain Injury After Intracerebral Hemorrhage in Rats

    Cell. Mol. Neurobiol.

    (2021)
  • Y.J. Jung et al.

    Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments

    Front. Cell Dev. Biol.

    (2019)
  • B. Balakrishnan et al.

    Nanomedicine in cerebral palsy

    Int. J. Nanomed.

    (2013)
  • J.K. Seok et al.

    Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules

    Front. Immunol.

    (2021)
  • V.M. Milenkovic et al.

    The Role of Chemokines in the Pathophysiology of Major Depressive Disorder

    Int. J. Mol. Sci.

    (2019)
  • N. Irrera et al.

    The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

    Int. J. Mol. Sci.

    (2020)
  • L. Xiao et al.

    Neuroinflammation Mediated by NLRP3 Inflammasome After Intracerebral Hemorrhage and Potential Therapeutic Targets

    Mol. Neurobiol.

    (2020)
  • H. Ren et al.

    Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage

    Stroke

    (2018)
  • S. Ismael et al.

    Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke

    Sci. Rep.

    (2018)
  • H. Zhao et al.

    Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats

    J. Neuroinflamm.

    (2017)
  • R.B. Tjalkens et al.

    Inflammatory Activation of Microglia and Astrocytes in Manganese Neurotoxicity

    Adv. Neurobiol.

    (2017)
  • N. Abe et al.

    Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

    Cells

    (2020)
  • P. Tiwari et al.

    Poly (ADP-ribose) polymerase: An Overview of Mechanistic Approaches and Therapeutic Opportunities in the Management of Stroke

    Neurochem. Res.

    (2022)
  • Y. Xiong, A. Mahmood, M. Chopp, Current understanding of neuroinflammation after traumatic brain injury and cell-based...
  • C. Betlazar et al.

    The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

    Cells

    (2020)
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      Citation Excerpt :

      Furthermore, leptin has been shown to have neuroprotective effects in cerebral ischemia and is usually regarded as a powerful and rapid stress mediator following injuries (Zhang et al., 2007). Leptin is essential for reducing the release of the excitatory neurotransmitter, protecting the mitochondria, lowering the production of superoxide’s and free radicals, raising the anti-inflammatory and anti-apoptotic activity (Zhang et al., 2019; Prabhakar et al., 2022). Leptin receptors were identified in the striatum, cortex, and hippocampus area of mice and cultured cortical neurons from rats (Zhang et al., 2007).

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