Protective Effects of Plant-Derived Compounds Against Traumatic Brain Injury

Abstract

Inflammation in the nervous system is one of the key features of many neurodegenerative diseases. It is increasingly being identified as a critical pathophysiological primitive mechanism associated with chronic neurodegenerative diseases following traumatic brain injury (TBI). Phytochemicals have a wide range of clinical properties due to their antioxidant and anti-inflammatory effects. Currently, there are few drugs available for the treatment of neurodegenerative diseases other than symptomatic relief. Numerous studies have shown that plant-derived compounds, in particular polyphenols, protect against various neurodegenerative diseases and are safe for consumption. Polyphenols exert protective effects on TBI via restoration of nuclear factor kappa B (NF-κB), toll-like receptor-4 (TLR4), and Nod-like receptor family proteins (NLRPs) pathways. In addition, these phytochemicals and their derivatives upregulate the phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/AKT) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, which have critical functions in modulating TBI symptoms. There is supporting evidence that medicinal plants and phytochemicals are protective in different TBI models, though future clinical trials are needed to clarify the precise mechanisms and functions of different polyphenolic compounds in TBI.

Introduction

There is a growing public health concern associated with traumatic brain injuries (TBIs) in people under 45 years of age. TBI is predicted to become the third most common cause of death worldwide by 2020, according to the World Health Organization (WHO) [1]. It is estimated that patients who survive severe TBI are permanently disabled in terms of neurological and psychological functioning and suffer a heavy financial burden. According to Wittchen et al., the costs associated with TBI exceed €33 billion annually in Europe alone, making TBI a key research area on many national agendas [2]. Despite advances in prevention and early resuscitation techniques, long-term neurological morbidity and overall neurological recovery remain major health challenges. To the best of our knowledge, there are currently no approved treatments for TBI that have been approved by any of the regulatory agencies in order to prove their effectiveness [3]. TBI is complex and heterogeneous, and conventional methods of diagnosing and treating it have proved inadequate. As a consequence, alternative methods for develo** TBI therapies should be explored [4].

Medicinal plant sand their bioactive ingredients, in particular polyphenols, have been implicated in various biological activities, including, but not limited to, immunomodulation, anti-inflammatory, cardiovascular protection, antioxidant, and anticancer potential [5,6,7]. It is well known that plants produce polyphenols in the form of glycoside esters and free aglycones. The polyphenol family contains more than 8000 structural variants [8]. Fruits and vegetables contain polyphenols, bioactive compounds responsible for their color, flavor, and health benefits. Based on their chemical structures, they can be divided into several different classes: flavonoids such as flavonols, flavones, isoflavones, neoflavonoids, anthocyanidins, chalcones, and proanthocyanidins, phenolic acids, stilbenoids and phenolic amides [9]. Multiple aromatic rings are attached to hydroxyl ligands to form these molecules, which are predominantly plant metabolites. They can be classified according to their chemical structures [10]. Antioxidants derived from polyphenolic compounds are mainly phenolic compounds derived from plants. Some of these compounds may exist as ester derivatives (e.g., epigallocatechin gallate) or ether derivatives (e.g., ferulic acid) [11]. A polyphenolic compound can be divided into two categories based on the type of phenolic compound it belongs to. In addition, these flavonoids have also been found in pharmaceutical preparations. Among those are epigallocatechin gallate, epigallocatechin, catechins, fisetin, luteolin, and quercetin, which are often used as ingredients in pharmaceutical preparations [12]. There is an active ingredient in Quercetin which inhibits the activity of BACE-1, which is a cleaving enzyme of the amyloid precursor protein [13]. In neurodegenerative diseases like Parkinson’s disease (PD), traumatic brain injury (TBI), and Alzheimer’s disease (AD), flavonoids and NSAIDs modulate the nuclear factor-kappa β (NF-κB) signaling pathway [14]. By scavenging free radicals, polyphenols protect against chronic diseases characterized by the involvement of free radicals in their pathogenesis. Some plant species, such as black soybeans, contain polyphenolic phytochemicals that are effective in maintaining human health, particularly in preventing cancer, neurological disorders, cardiovascular disease, and diabetes. However, their effect on the progression of TBI is controversial, perhaps because of the irreversible brain damage following TBI [15]. A review of various in vitro and in vivo studies on the therapeutic benefits of plant-derived phyotchemicals, with curcumin as an example, in TBI has been presented in this review (Fig. 1).

Fig. 1

Therapeutic advantages of curcumin, a polyphenol, against traumatic brain injury through interaction with different inflammatory signaling pathways and their effects on levels of cytokines and related biomarkers

Pathogenesis of TBI

There has been a rapid increase in TBIs and they are considered a highly complex condition. Accidents involving motor vehicles, abuse, and concussions are among the leading causes of TBI. According to research, there are three levels of severity associated with this disease, mild, moderate, and severe. During recovery, there is sometimes a debilitating and transient neurological disorder. While injuries to other parts of the body contribute significantly to brain damage in severe cases such as polytrauma, injuries to the brain can cause even more significant damage [16].

There are several injuries that can result from TBI, including primary and secondary injuries. Besides lacerations and contusions, primary injuries can result in hemorrhages and ruptures. In addition to the primary injury caused by the traumatic event itself, the secondary injuries that develop as a result of inflammation, oxidative stress, and glutamate toxicity have been shown to play a significant role in determining the outcome of a traumatic brain injury. Edema and cell death occur in the brain due to calcium imbalance and oxidative stress after a post-TBI injury [17]. Often, secondary injury is observed within a few hours to a few days of the initial injury due to a cascade of events. After the primary injury mechanism is triggered, a second wave of pathological changes, commonly known as secondary injury mechanisms, is initiated, including metabolic changes, neuronal inflammation, vascular complications, cell death of glia and neurons, axonal damage, and mitochondrial dysfunction. Damaged mitochondria produce large amounts of oxygen near the site of injury. Autophagy destroys these mitochondria for relative neuronal protection and reduces oxidative stress [18, 19]. In neurons that have been damaged by cell death proteins such as those associated with mitochondrial apoptosis are triggered when mitochondrial membranes are damaged and permeability increases. Autophagy is one of the processes in the starvation response that is regulated by the organ and is responsible for the destruction and recycling of cellular components, as well as participating in organ circulation and controlling bioenergetics in the body [20]. Furthermore, autophagy prevents mitochondrial apoptosis or neuroinflammation, in addition to its neuroprotective effects. Furthermore, it is also important to note that excessive autophagy can also contribute to the generation of neuronal death when there are ischemic or hypoxic conditions, although its inhibition does the opposite.

Some signaling pathways such as phosphatidylinositol 3-kinase/ protein kinase B (PI3K/AKT), are involved in apoptosis, and induction of this pathway can suppress it post-TBI [21]. The secondary injury that results from TBI is characterized by an array of inflammatory responses. The Toll-like Receptors (TLRs) in the human immune system are located on the surface of the cells and are responsible for activating the immune system by releasing endogenous ligands and recognizing a wide range of pathogen-associated molecular patterns (PAMPs), including lipopolysaccharides (LPS) flagellin, and single-stranded and double-stranded viral RNA. Multiple aspects of CNS homeostasis are affected by these patterns, which release enzymes and cytokines that trigger an inflammatory cascade [22]. There is increasing evidence that TLR4 plays a critical role in the initiation of inflammatory responses after trauma. TLRs activate two distinct pathways leading to the activation of transcription factors that regulate the expression of pro-inflammatory cytokine genes. Myeloid differentiation factor 88 (Myd88) activates the TNF receptor-associated factor 6 (TRAF6), producing pro-inflammatory cytokines. There is an interaction between adapter-inducing interferons (TRIF) that contain TIR domains, which are activated in a pathway independent of Myd88, and induce nuclear factor kappa B (NF-κB) to produce inflammatory mediators [23, 24].

The NF-κB family consists of five proteins, including NF-κB1 (p50), NF-κB2 (p52), p65, RELB, and c-REL. Both endogenous and exogenous ligands activate NF-κB and, when activated, is found in neurons and glia under various \inflammatory conditions. In addition to the canonical pathway, a non-canonical pathway activates NF-κB [25]. The NF-κB pathway is also involved in a wide range of immune responses and various cellular progressions such as apoptosis and proliferation. As a result of TBI, activation of NF-κB releases several inflammatory agents that lead to secondary brain damage [26]. A recent study has shown that TBI exacerbates oxidative stress by producing free radicals [27]. There is increasing evidence that oxidative stress plays an important role in secondary damage in relation to primary damage. The nuclear factor erythroid 2 related factor 2 (Nrf2) is involved in a variety of functions within cells and accumulates in their cytoplasm under normal conditions [28]. In addition to regulating genes involved in oxidative stress, Nrf2 acts as a transcription factor. As a result of this component of Nrf2, antioxidant enzymes such as malondialdehyde (MDA), heme oxygenase-1 (HO1), superoxide dismutase (SOD), quinone oxidoreductase-1 (NQO1), and glutathione peroxidase (GSH-Px) are activated [29]. This enzyme acts by directly regulating the levels of reactive oxygen species (ROS), meaning that it can directly react with free radicals without harming the cells' vital function. The antioxidant response element (ARE) found in the gene promoter allows Nrf2 to promote the expression of antioxidant genes. The Nrf2/ARE signaling pathway modulates several pathological processes, including oxidative stress [29, 30].

Effect of Different Phytochemicals and Polyphenols on TBI Through Inflammatory Signaling Pathways

Polyphenols exert antioxidant activity through various mechanisms, some of which are multi-step mechanisms [31]. However, free radical scavenging is widely recognized as one mechanism by which polyphenols exert their antioxidant effects. The extended conjugation of the unpaired electron is another key property of polyphenolic antioxidant radicals that contributes to their increased stability. By quenching the reactive nitrogen species (RNS) and reactive oxygen species (ROS) produced by free radicals as they pass through a polyphenolic compound, polyphenolic compounds manifest their antioxidant benefits [32].

As a result of free radical oxidation, ROS, RNS, and other compounds are produced. The ROS and RNS commonly observed in free radical-induced oxidative damage include nitric oxide (·NO), hydroxyl radicals (·OH), superoxide radicals (O₂^–), and peroxynitrite anion (O = NOO^–). Fenton reactions catalyzed by metal ions (e.g., Fe²⁺ and Cu⁺) generate ROS and RNS. When ROS and RNS are subjected to high levels of oxidative stress, they are highly reactive and have short half-lives, which, in conjunction with an imbalance between their production and destruction, can cause a significant amount of protein modifications as well as other reaction products to accumulate at the site of inflammation as a result of ROS and RNS-derived proteins. Inflammatory conditions such as cancer, atherosclerosis, AD, and traumatic brain injury may arise as a result of an excessive accumulation of ROS and RNS-derived reaction products [33,34,35]. In addition to polyphenols, citrus flavanones, including hesperetin, hesperidin, and neohesperidin, can cross the blood–brain barrier (BBB). BBB permeability varies between polyphenols. In addition, animal studies has shown that blueberry consumption induces anthocyanin accumulation in the cortex and cerebellum of animal models (rats and pigs) [36]. Furthermore, the valerolactones undergo further metabolism resulting in the formation of phenolics and polyphenols, such as (hydroxyaryl)propanoic acid, (hydroxyaryl) cinmmic acid, (hydroxyaryl)valeric acid, hydroxybenzoic acid, and (hydroxyaryl)acetic acid derivatives. Secondary polyphenolic metabolites have a relatively higher degree of bioavailability and are more permeable to the BBB than flavonoids or dietary flavonoids and may inhibit neuroinflammation. As a result, polyphenols can be used therapeutically in a wide range of neurodegenerative diseases as well as TBI (Table 1 and 2) [37, 38].

Table 1 In vivo interventions

Table 2 In vitro interventions

Curcumin

The recent findings on curcumin demonstrate its remarkable versatility as a molecule that interacts with a variety of molecular targets [39,40,41,42,43,44,45,46,47,48]. There are curcumin compounds in the rhizomes of the turmeric plant (Curcuma longa), a plant belonging to the Zingiberaceae family. As an antioxidant, anti-infection, anti-inflammatory, and anti-tumor compound, curcumin has been approved by the United States Food and Drug Administration as a safe compound [49]. Various CNS disease models have been shown to be susceptible to curcumin's anti-inflammatory properties, including intracerebral hemorrhage, global brain ischemia, and neurodegeneration, all of which are associated with the inflammation of the CNS. Similarly, curcumin exerts neuroprotective effects in mammals when it crosses the blood–brain barrier. An experiment in mice modeling spinal and bulbar muscular atrophy revealed that 5-hydroxy-1,7-bis (3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one inhibited the aggregation of pathogenic androgen receptors. Curcumin is suspected to possess neuroprotective properties, but few studies have explored this possibility [49]. Curcumin has been shown to reduce cerebral edema, enhance membrane and energy homeostasis, and influence synaptic plasticity following TBI in a few studies. However, curcumin does not appear to have any immunomodulatory properties on inflammatory reactions.

Curcumin has been shown by numerous studies to be effective in reducing inflammation [50, 51]. A lot of research has shown that curcumin suppresses the activation of NF-κB by inhibiting the phosphorylation and degradation of IκB; as a result, curcumin reduces the inflammation caused by NF-κB. The effects of curcumin have been shown to be not only reduced post-TBI neuroinflammation, but also decreased levels of inflammatory mediators that are produced following a TBI [52]. The anti-inflammatory effects of curcumin were demonstrated in an in vitro study using 100 mg/kg of curcumin [

Data Availability

This is a review article and there is no associated primary data.