Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches
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
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Funding
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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.
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2023, Neuroscience ResearchCitation 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).