Introduction

Brain damage and behavioral abnormalities that characterize brain diseases impose a significant medical burden and degrade both the quality of life for patients and their families [1]. Neuroinflammation, oxidative stress, transcriptional alterations, abnormal protein deposition, and excitotoxicity are a few of the major causes of brain diseases [2]. Multiple brain diseases have been linked to the onset and progression of oxidative stress [3]. Oxidative stress and oxidative stress-associated neuroinflammation are widely acknowledged causative factors in many brain diseases, including AD, stroke, depression, PD, etc. [4]. Oxidative stress is caused by an imbalance between the production of radical species and antioxidant systems, which is linked to the development and progression of diseases. Emerging researches have confirmed that tBHQ has been shown to reduce oxidative stress to exert neuroprotection in a number of brain diseases [5,6,7].

TBHQ is a very effective synthetic oil-soluble phenolic antioxidant with a significant antioxidant action, which has a low toxicity, low dosage, high-temperature resistance, antibacterial, low cost, among other properties (Fig. 1). Due to its excellent antioxidant activity and safety, tBHQ can also defend against oxidative stress and inflammation-induced dysfunction in animal cells and tissues [8,9,10]. TBHQ is an inducer of Nrf2 which is crucial for innate immune response regulation [11, 12], and when the body is stimulated by external stimuli, Nrf2 regulates the expression of related inflammatory factors by regulating the activity of the NF-κB signaling pathway [13]. TBHQ exerts antioxidant damage and neuroprotective effects on the central nervous system by increasing the stability of Nrf2 protein and activating Nrf2 transcription [14] (Fig. 2).

Fig. 1
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Characters of tBHQ

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Fig. 2
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Antioxidative stress and neuroprotective mechanisms of tBHQ

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Effect of tBHQ on Inflammation

Inflammation is the body’s natural defense mechanism and innate immunological reaction to outside stimuli, which is a protective response brought on by a damaging factor that affects the vascular system’s live tissues and has the potential to harm healthy tissues as well. The immune system, metabolism, and endocrine system will all be negatively impacted by an excessive inflammatory response, which is exceedingly damaging to health. Pro-inflammatory cytokines [15, 16], anti-inflammatory cytokines [17], and other nonspecific inflammatory cytokines [18] are among the inflammatory components that contribute to inflammatory reactions. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-18, and interferon (IFN)-γ are the primary pro-inflammatory cytokines that play a key role in immune activation and causing inflammation. IL-4, IL-10, IL-13, transforming growth factor (TGF)-β, IL-1 receptor antagonist (IL-1Ra), and soluble receptors of various pro-inflammatory cytokines are anti-inflammatory cytokines that primarily suppress immunity and inflammation. Complex cytokine networks and immune cells are created by pro- and anti-inflammatory cytokines, and their dynamic equilibrium influences the course of inflammation and its outcome [19, 20].

TBHQ can inhibit inflammation and is crucial in the treatment of several illnesses. It is widely known that alterations in Nrf2-dependent redox homeostasis are closely correlated with inflammation [21]. As an illustration, it has been proven that tBHQ alleviates inflammation caused by fine particulate matter by promoting the transcriptional activity of Nrf2 [22]. NF-κB, pro-inflammatory cytokines, and intercellular adhesion molecule-1 (ICAM-1) are just a few of the inflammatory-related factors that tBHQ significantly reduces in the intestine [23, 24], which can prevent intestinal inflammation after traumatic brain injury (TBI) by activating the Nrf2 signaling pathway and lessen mucosal damage [23]. TBHQ alleviates oxidative stress during myocardial ischemia and reperfusion by inducing secretion of anti-inflammatory cytokines [25], which by increasing the activity of Nrf2 in macrophages and vascular smooth muscle cells in atherosclerotic lesions [26] inhibited the expression of cytokine induced pro-inflammatory and oxidative stress genes, changed the phenotype of macrophages, promoted autophagic activity, significantly reduced the size, extension and lipid content of atherosclerotic plaques, and reduced the size of macrophages and foam cells and the expression of chemokines to alleviate inflammation, so as to provide a method for the protection of atherosclerosis in diabetes. Moreover, in high salt-induced hypertension experiments [27], tBHQ increased the expression of Nrf2 in paraventricular nucleus (PVN), reduced oxidative stress, the expression of IL-1β and IL-6, and the neuronal activity and the plasma level of norepinephrine to reduce salt-induced hypertension and cardiac hypertrophy in hypertensive rats, inhibited the activation of NF-κB, that was demonstrated that tBHQ had a protective effect on high salt-induced hypertension by inhibiting oxidative stress and inflammation in PVN. The toll-like receptor 4 (TLR4)-NF-κB axis may be activated by oxidative stress, inflammation, and renal tubular cell apoptosis, which might aggravate renal ischemia/reperfusion (I/R) injury (RI/RI). However, by boosting antioxidant capacity and helpful inflammatory response modulation, tBHQ [28] might lessen the expression of pro-inflammatory cytokines and pro-apoptotic proteins, suppress the NF-κB signaling pathway, and lower the RI/RI of diabetic rats. On one hand, tBHQ alleviated oxidative abnormalities, reduced malondialdehyde (MDA) content, and increased superoxide dismutase (SOD) activity. On the other hand, the levels of TNF-α and IL-1β were decreased; concurrently, it also decreased the expression of pro-apoptotic proteins and increased the expression of beta cell lymphoma-2. TBHQ intervention dramatically reduced oxidative stress by up-regulating Nrf2 gene, suppressing inflammation, apoptosis, and promoting proliferation of testicular germ cells; more importantly, tBHQ could prevent probable long-term reproductive failure associated with medications [10]; simultaneously, in order to strengthen the body's antioxidant defense system both before and after cisplatin chemotherapy, tBHQ also raised steroidogenesis and enhanced sperm parameters.

Effect of tBHQ on Oxidative Stress

The idea of oxidative stress was initially put forth in 1985 as a redox biology and medicine concept and was derived from human understanding of aging. Highly reactive molecules including reactive oxygen species (ROS) and reactive nitrogen species (RNS) are overproduced in the organism when oxidative stress takes place [29,30,31,32]. When the production of intracellular ROS exceeds the ability of antioxidant system to scavenge ROS, excessive ROS not only attacks biological macromolecules such as proteins, lipids, and DNA to result in cell death or changes in organizational structure but also damages cells by causing mitochondrial dysfunction, which is one of the causes of neurodegenerative diseases, such as AD and PD. In order to create a dynamic physiological equilibrium, the body’s oxidation and antioxidant systems interact and restrain one another. The state of oxidative stress is demonstrated when the antioxidant system is compromised or when the oxidative system is strengthened. The oxidation system, which causes oxidative damage to cells, is mostly made up of reactive free radicals like ROS and RNS, including superoxide anion, hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide (NO), nitrogen dioxide, and nitrite peroxide [33,34,35], which causes oxidative damage to cells. Among them, mitochondria is susceptible to oxidative stress [36], which is the biggest cause of ROS production [37]. To scavenge ROS and guard cells from oxidative damage, the antioxidant system uses both enzymatic antioxidants like SOD, catalase (CAT), glutathione peroxidase (GPx), and peroxidase oxidoreductase as well as non-enzymatic antioxidants. As a result of the combination of internal and external stimuli, oxidative stress is currently thought to be one of the key mechanisms causing clinical damage in a number of diseases [38]. TBHQ significantly attenuated the production of oxidative products and inflammatory cytokines, increased GPx and SOD levels, decreased NF-κB, which protected against oxidative damage, and restored the antioxidant mechanism [39, 40]. Nrf2-Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response elements (ARE) pathway has been linked to oxidative stress-related diseases [41], such as cancer, neurodegenerative diseases, diabetes and others [42, 43]. Nevertheless, tBHQ is one of the most effective activators of signaling pathways and plays a significant antioxidant role by activating the pathway [10, 44, 45].

According to research on ventilator-induced lung injury (VILI) [46], tBHQ increased pulmonary redox capacity by activating the Nrf2-ARE pathway, increased the expression of Nrf2-dependent genes like Nrf2 and SOD1, and the expression of antioxidant genes, all of which had a protective effect on VILI. For oxidative stress-induced osteoarthritis, tBHQ can improve the viability of chondrocytes, reduce excessive ROS production, raise SOD levels and lower MDA levels, reduce oxidative stress-induced mitochondrial damage and apoptosis, improve oxidative stress-induced matrix degradation, and activate Nrf2 signaling pathway, that indicated that tBHQ could prevent oxidative stress-induced chondrocyte apoptosis and extracellular matrix degradation in vitro, which had the potential to treat osteoarthritis [44]. Methamphetamine (MA) induces cardiotoxicity, neurotoxicity and pulmonary toxicity through oxidative stress, while tBHQ may inhibit oxidative stress-induced neurotoxicity through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, astrocyte activation, and glutathione (GSH) pathway [47]; the up-regulation of Nrf2 expression to reverse the overexpression and phosphorylation of protein kinase-like ER kinase (PERK), alleviated MA-induced oxidative stress, and accelerated endoplasmic reticulum stress to initiate PERK-dependent apoptosis [48]. TBHQ may become a promising treatment medication for hyperlipidemia in chronic renal disease and lessen liver damage by inhibiting Nrf2/heme oxygenase-1 (HO-1) pathway-induced oxidative stress damage and lipid deposition and enhancing antioxidant defense [45, 49]. TBHQ inhibited lipopolysaccharide (LPS)-induced ROS production and macrophage repolarization, which significantly protected LPS-induced ROS accumulation in a dose-dependent manner; inhibited the activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, and IL-1β-induced chondrocyte apoptosis, inflammation and differentiation defects, that experimental studies in vitro showed that tBHQ may prevent osteoarthritis from developing [9]. To protect pheochromocytoma cells from oxidative stress, inflammation, apoptosis, as well as oxidation-redox imbalance, tBHQ activated the Nrf2/ARE pathway, stabilized Nrf2, raised the expression of HO-1 and γ-glutamylcysteine synthetase, and enhanced the expression of HO-1 [50,51,52]. Simultaneously, tBHQ simultaneously decreased MDA and ROS levels, raised SOD and GPx activity, suppressed oxidative stress by raising Nrf2 levels, and activated Nrf2 to lower gestational diabetes mellitus [53]. Additionally, tBHQ may be employed as a potential neuroprotectant and adjuvant therapy for patients with traumatic brain damage (TBI) due to its ability to drastically attenuate NADPH oxidase protein expression, decrease MDA level, increase Nrf2 protein level, and activate the antioxidant enzyme SOD [54].

TBHQ in Brain Diseases

TBHQ, Neuroinflammation, Oxidative Stress, and AD

AD is one of the most prevalent neurodegenerative brain diseases characterized by progressive memory impairment, neuronal loss, tau hyperphosphorylation-induced neurofibrillary tangles, and extracellular amyloid β-protein (Aβ) accumulation-induced amyloid plaques [55, 56]. Millions of people all over the world are severely impacted by AD, and primarily affects the elderly and is characterized by progressive cognitive dysfunction and behavioral disorders, which is mainly manifested as systemic dementia such as cognitive decline, mental symptoms, and behavioral disorders, also causes a gradual loss of daily living skills [57]. Despite significant research efforts, there is still no effective therapy strategy for AD since the precise etiology and pathology of the disease are still unknown [58, 59]. Intriguingly, tBHQ's positive effects on AD were found in both in vivo and in vitro experiments [60]. In the brain and hippocampus of AβPP/PS1 mice, for instance, a 6-week tBHQ diet significantly decreased Aβ deposition. Notably, this effect was not due to the changes in AβPP expression/processing or Aβ production but the improved Aβ clearance, including increased Aβ degradation and Aβ efflux from the affected brain [60]. A further mechanistic investigation found that tBHQ could suppress the expression of plasminogen activator inhibitor-1 and enhance the activities of plasminogen activators, which significantly promote Aβ degradation in the brain of AβPP/PS1 mice [60]. Moreover, the increased expression of low-density lipoprotein receptor-related protein 1, a protein involved in Aβ efflux transport out of the brain, suggested that the improved Aβ efflux transport from the brain following tBHQ treatment contributes to the alleviation of Aβ load in AD mice. Furthermore, the antioxidant capacity of tBHQ also contributes to the improved AD pathology, as evidenced by increased concentration of GSH and decreased lipid peroxidation level in the transgenic AD mice, that indicates tBHQ has a neuroprotective effect on AD. NT2N is a well-documented cell line generating intracellular Aβ and is widely used in AD in vitro studies [61]. Intriguingly, NT2N neurons pretreated with tBHQ significantly reduced oxidative stress-induced Aβ production and markedly suppressed neuronal apoptosis. In fact, tBHQ’s neuroprotection depends on the Keap1-Nrf2 pathway, which is the main protective route in response to oxidative stress. Under normal conditions, Nrf2 binds to its inhibitor Keap1. However, in the presence of oxidative stress, Nrf2 dissociates from Keap1 and trans-locates into the nuclear, triggering an antioxidant response. The Keap1-Nrf2 pathway is stimulated by tBHQ, and the amount of Nrf2 in neuronal nuclei increases considerably, indicating an antioxidant response to tBHQ [61]. In line with these findings, tBHQ induced the elevated GSH levels and buffered the oxidative regents-induced redox status changes in NT2N neurons [61], indicating that the antioxidant effect of tBHQ contributes to the beneficial effects of tBHQ in AD. The neuroprotective effects of tBHQ are influenced by alterations in FoxO3a translocation as well as Nrf2 nuclear translocation. Following translocation from the cytosol to the nucleus, FoxO3a as one of the forkhead transcription factors to cause neuronal apoptosis [62]. Unlike promoting nuclear translocation of Nrf2, tBHQ suppressed nuclear translocation Nrf2 and activity by promoting phosphatidylinositol 3-kinase (PI3K)-AKT signaling activation-induced FoxO3a phosphorylation.

TBHQ, Neuroinflammation, Oxidative Stress, and Stroke

Stroke is the “number one killer” of people’s health and poses a major threat to human life. There are usually no obvious clinical symptoms prior to the onset of a stroke, but once the attack occurs, there is a high mortality rate, a high disability rate, and a high treatment cost, all of which pose a serious threat to public health [63]. Stroke is a type of acute cerebrovascular disease that includes both ischemic stroke and hemorrhagic stroke. Strokes are a collection of illnesses that result in hypoxia and ischemia of the brain tissue in the blood supply area. The damage to brain tissue is caused by sudden blood vessel rupture in the brain or by the inability of blood to flow into the brain owing to vascular blockage [64]. Ischemic stroke, which makes up around 70% of all strokes, is the most significant form of stroke among them [65]. Stroke with symptoms such as acute or sudden loss of balance or coordination, blurred vision, facial numbness or crooked eyes, limb weakness, trouble speaking, etc. [66]. Stroke is caused by a variety of reasons, both internal and external. Excitatory amino acid toxicity [67], free radical damage [68], inflammatory response [69], expression of related apoptosis genes [70], and immunosuppression [71] are the key contributors to the pathophysiology of ischemic stroke.

Both neuroinflammation and oxidative stress play significant roles in the development of stroke lesions, with neuroinflammation playing a complicated and multidimensional function in ischemic stroke [72]. Microglia are triggered by a variety of inflammatory signals to release pro-inflammatory cytokines like TNF-α, adhesion molecules, IL-18, and ROS, which exacerbate brain injury [73, 74]. Microglia and astrocytes can be rapidly activated within minutes after ischemic stroke [75] and produce a large number of pro-inflammatory mediators that worsen tissue damage [76] and lead to neutrophil infiltration in the brain [77]. The number and expression of astrocytes significantly increase in response to ischemic injury, release a variety of pro-inflammatory factors and induce the synthesis of NO synthase which the activation of astrocytes promoted the recovery process of the slow development of the whole brain and simultaneously microglia response was involved in local repair and cell debris removal [78]. However, the nerves were harmed by the neuronal degeneration brought on by a significant amount of pro-inflammatory substances generated by excessively active astrocytes [79]. JAK/STAT [80], MAPK [81], NF-κB [82], Toll-like receptors (TLRs)/myeloid differentiation primary response gene 88 (MyD88) [83], and other important signaling pathways in cells after stroke mediated inflammatory reactions. Additionally, cell adhesion molecules [84], chemokines [85], and blood–brain barrier [86] also play important roles in inflammation. One of the main causes of tissue damage in stroke is the excessive generation of ROS, which builds up in the body during a stroke, induces oxidative stress, and sets off a chain reaction of biological responses [87, 88]. Free radicals produced as a result of oxidative stress, particularly the high levels of ROS and RNS that caused protein malfunction, DNA damage, and lipid peroxidation, which ultimately led to cell death [68].

Nrf2, a protein that is biologically connected to the brain and has a role in tBHQ’s function, reduces the severity of local ischemic brain injury. The effects of tBHQ on GSH levels in the cortex and the basic and induced antioxidant/detoxifying enzyme activities in Nrf2(-/-) mice demonstrate that Nrf2 activation protects the brain from cerebral ischemia in the body, suggesting that activating Nrf2 may be a useful preventive treatment for patients who are at risk for stroke [89]. A study using a neonatal hypoxic-ischemic (HI) rat model was conducted to determine whether tBHQ offered protection against oxidative stress in neonatal HI brain injury. The findings [5] revealed that tBHQ activated the Nrf2-mediated antioxidant signaling pathway, reduced oxidative stress index, enhanced Nrf2 nuclear accumulation and DNA binding activity, and up-regulated the expression of Nrf2 downstream antioxidant genes, with the exception of the fact that it inhibited reactive. Through the activation of AKT [90] and the IL-10-mediated astrocytes pathway, tBHQ increased ischemic-induced angiogenesis, which may offer therapeutic guidance for the treatment intervention following oxidative stress injury such as ischemic stroke [91]. What is more, after cerebral ischemia, tBHQ increased angiogenesis and astrocyte activation by activating the Nrf2 pathway, increased HO-1 expression, and controlled the expression of vascular endothelial growth factor through the Nrf2/HO-1 pathway, in order to promote angiogenesis and enhance functional recovery [92]. Despite the fact that tBHQ accelerated the activation of the Nrf2-ARE signaling cascade, this activation would wane with continued exposure to tBHQ [93]. Intriguingly, tBHQ significantly reduced the mitochondrial respiration of cerebral cortical endothelial cells in vitro, and the induced mitochondrial inhibition could be enhanced in the presence of other mitochondrial toxins like LPS. The blood–brain barrier would be destroyed by LPS when the cerebral vascular endothelial cells’ mitochondrial function was compromised, aggravating the effects of a stroke and creating a negative consequence of tBHQ-enhanced mortality from permanent stroke [94, 95].

TBHQ, Neuroinflammation, Oxidative Stress, and Depression

One of the most prevalent psychological and mental diseases, depression is characterized by low mood, lack of interest in activities, poor focus, and slow thinking [96]. Depression is one of the most severe disease burdens of non-fatal neuropsychiatric disorders and is projected to be in the top three of all diseases burdens by 2030 [97], which seriously impairs the quality of life and brings a heavy burden to the affected patients and their families. Typical pathophysiological characteristics of depression include deficits in monoamine neurotransmission, resistance of glucocorticoid receptors, impaired neurotrophic factors, increased glutamate, corticosteroid-releasing hormone, and cortisol, and various hypotheses have been developed based on those pathophysiological changes, including the most widely accepted monoamine hypothesis [98]. Recently, growing evidence reveals that neuroinflammation is crucial for the emergence of depression, and anti-inflammatory treatments greatly reduced depressive-like symptoms [99, 100].

It is commonly acknowledged that neuroinflammation may play a role in the etiology of depression [101]. The neuro-inflammatory response mechanism is crucial to the development of depression, and it may alter the neurological function of the depression-related brain region through mechanisms including mitochondria and energy metabolism, resulting in aberrant emotional regulation [102, 103]. In some cases, microglia, astrocytes, and certain cytokines involved in the neuroinflammation process, which primarily manifests as the activation of microglia and astrocytes and the alteration of chemokine levels, may have abnormal effects that contribute to the development of depression [104,105,106]. Patients with depression had significantly higher levels of cytokines, macrophages, microglia, and astrocyte carbon monoxide synthase in their brains [107]. The prevalence and progression of depression are influenced by the balance of M1 type (classical/pro-inflammatory activation) and M2 type (alternative/anti-inflammatory activation) present in microglia [108], among which pro-inflammatory factors are involved in immune activation, and the occurrence of inflammation is positively correlated with the severity of depressive symptoms [109, 110]. The amount of TNF-α in the serum of depressive patients is markedly elevated [111], which may cause apoptosis through associated pathways [112] and influence specific chemicals that can affect depression by affecting those that can cross the blood–brain barrier [113]. The NF-κB signal transduction pathway and the expression of hippocampal neural progenitor cells are both impacted by IL-1β, which also reduces the proliferation of hippocampal cells [114], and participates in inflammatory responses that damage nerve cells in the brain [115]. IL-1β is a key mediator of depression. Fortunately, IL-4 therapy was able to block IL-1β-induced central nervous system glial activation and neurotransmitter changes, hence modulating IL-1β-induced depressive behavior [116]. Additionally, depressed patients had blood levels of IL-6 that were noticeably raised [117], which had neurotoxic effects on the brain by way of a variety of physiological stressors that led to structural and functional abnormalities. However, a research found that the levels of IL-1β and IL-6 in peripheral blood of the elderly with depression increased, while TNF-α levels did not rise [118]. The pathogenic process of depression involves oxidative stress, patients with depression experience an imbalance of oxidative stress, and changes in oxidative stress markers are linked to changes in the course and symptoms of depression [119, 120]. In the brains of depressed patients, lowered GSH levels fell [121], MDA and NO levels rose [122], which either directly or indirectly contributed to the development of depression. By controlling mitochondrial function to cause disorder, excessive autophagy to hasten the aging of brain neurons, and altering the function of the hippocampus, among other things, oxidative stress may have a role in the development of depression [123, 124]. Mitochondria are the susceptible sites of depression [103] and abnormal mitochondrial energy metabolism is involved in the occurrence of depression, mainly including the following aspects: the reduction of mitochondrial adenosine triphosphate (ATP) [125], the activity change of mitochondrial oxidative respiratory chain and its complex [126, 127], oxidative stress injury [128], abnormal mitochondrial morphological structure [129], mitochondrial related genes and molecular level abnormalities [130, 131] to result in a series of reactions such as mitochondrial dysfunction to affect brain function. A new ATP-sensitive potassium channel opener-Iptakalim could upregulate postsynaptic density 95 and synaptophysin, alleviate synaptic structural damage, reverse abnormal mitochondrial fission and fusion, and reduce mitochondrial ATP production and mitochondrial membrane potential collapse in depression models to alleviate abnormal mitochondrial dynamics and function dependent on mitochondrial ATP, which is helpful to improve synaptic plasticity and play an antidepressant role [132]. Moreover, mitochondrial transplantation was able to ameliorate LPS-induced depression-like behaviors, increase the expression of brain-derived neurotrophic factor and neurogenesis, and restore dysfunction of ATP production and oxidative stress in inflammation-induced depression, whose results suggest that mitochondrial transplantation may one day be used as a new treatment for major depressive disorder [133].

Studies have indicated that [6] Nrf2/PI3K may play a key role in the relationship between oxidative stress and apoptosis in MA-induced chronic neurotoxicity, which can result in the development of depressive-like behavior. However, tBHQ could amplify effect on the Nrf2/HO-1 pathway and protect dopamine (DA) neurons from MA-induced neurotoxicity, as result of reducing oxidative stress, protecting the normal signal transduction of PI3K/AKT pathway and the anti-apoptotic ability of PI3K/AKT; at the same time, PI3K/AKT pathway increased the immune content of Nrf2 protein and further enhanced antioxidant capacity through Nrf2/HO-1 pathway. Ghosh et al. [21] injected LPS into the abdominal cavity of Swiss albino mice to induce peripheral inflammation, which caused depression-like behavior in mice, increased the activation of microglia and the level of pro-inflammatory cytokines, and activated NF-κB-p65 pathway, after tBHQ is used, the changes of autophagy and cell death pathways in hippocampus were alleviated, and depression-like symptoms were reversed by activating Nrf2-dependent gene expression. Additionally, through activating the Nrf2/ARE pathway, tBHQ could reduce depressive and anxiety-like behaviors in diabetic rats [134].

TBHQ, Neuroinflammation, Oxidative Stress, and PD

PD, also referred to as “tremor paralysis,” is a prevalent neurodegenerative illness among the elderly and is the second most frequent neurodegenerative disease in this population. Clinically, the predominant symptoms are the static tremor, motor retardation, myotonia, postural and gait disorders, which are often accompanied by non-motor symptoms including depression, anxiety, constipation, autonomic nerve dysfunction, and so on [135]. The loss of the nigrostriatal pathway, which is primarily correlated with significantly decreased levels of DA and aggregation and misfolding of α-synuclein (α-syn) is the primary PD manifestation [136, 137]. In addition to factors including aging, environmental factors, familial inheritance, genetic mutations, and environmental factors, the etiology and pathophysiology of PD are extremely complicated and are yet unclear [138]. The abnormal regulation of α-syn, mitochondrial dysfunction, oxidative stress, excessive immune-inflammatory mechanisms, excessive accumulation of byproducts of DA oxidative metabolism, gastrointestinal related dysfunction, neurotoxicity, etc. are the main components of the pathogenesis of PD [139,140,141,142,143,144,145]. So far, there is no cure for PD but only to relieve its symptoms.

The process of neuroinflammation involves a wide number of enzymes and receptors, and the activation of microglia and astrocytes in the substantia nigra associated with neuroinflammation is thought to have a significant role in PD [146]. Numerous intracellular enzymes, including NADPH oxidase, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO), are activated to varying degrees when glial cells are stimulated, and a large number of inflammatory factors, including ROS, prostaglandin (PG), NO and hypochlorous acid are released, which can harm or even kill neurons. A huge quantity of oxygen free radicals and a range of pro-inflammatory cytokines can be produced by activated microglia, which can lead to the death and distortion of neurons [147,148,149]. What is even more remarkable is that dead neuron fragments can continue to promote microglial activation [150] to form a self-promoting vicious cycle to impel the malignant development of PD. A significant part of the pathophysiology of PD is attributed to astrocyte activation, which is connected to the PD pathogenesis. Under the influence of specific stimulating conditions, astrocytes release several pro-inflammatory substances that damage dopaminergic neurons and aid in the onset and progression of PD [151, 152]. The loss of DA neurons in the substantia nigra was finally caused by the oxidative stress and excitotoxicity of the astrocytes implicated in PD, and the expression of a number of proteins was important in the development of PD [153, 154]. Numerous studies have demonstrated the tight connection between oxidative stress and the onset and progression of PD [141]. Basic research and postmortem findings showed that oxidative stress, which was crucial in the degradation of PD DA neurons, was directly associated to the degeneration or death of dopaminergic neurons in the brain's substantia nigra [123, 155]. The etiology of PD is influenced by oxidative stress, which is correlated with a drop in GSH levels [156], a drop in SOD and CAT activity [157], a deficiency in mitochondrial complex I [158], and a significant amount of oxidized lipids, proteins, and DNA [156,157,158,159].

DA-induced oxidative stress may be directly associated to the pathophysiology of PD, and therapy with tBHQ may boost SH-SY5Y cells' intracellular antioxidant capacity to shield cells from 6-hydroxydopamine (6-OHDA)-induced oxidative stress, which plays a neuroprotective role, increases the intracellular GSH level and induces the expression of NADPH: quinone oxidoreductase (NQO1) mRNA [160]. Meanwhile, tBHQ had the ability to reverse oxidative stress such as cytoplasmic swelling, interstitial edema and neuronal loss induced by 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine(2’CH3-MPTP) in mice; increased GSH brainstem content and reduce the MDA and SOD activity levels, while diminished histopathology and histochemical alterations may have beneficial benefits in exploring the genesis and pathogenic variables associated to dopaminergic damage and providing a direction for the research of PD treatment [161]. By activating the Nrf2/ARE pathway and Nrf2/ARE pathway to offer a direction for minimizing or preventing PD cell death, tBHQ was shown in another study to be able to protect 6-OHDA-induced damage in live mice [162]. Another experimental study revealed that cortical astrocytes from aged rats can respond to tBHQ pretreatment and stimulate the Nrf2-antioxidant response pathway to induce antioxidant strategies against MPP + (1-methyl-4-phenylpyridinium) toxicity, increase antioxidant enzymes and form cell protection, which is of great significance for the development and prevention or counteraction of diseases involving oxidative stress, such as AD, PD or other diseases [163].

Conclusion

In conclusion, tBHQ has neuroprotective effects on brain diseases through anti-inflammatory, anti-oxidative stress, and inhibition of apoptotic protein expression, among which, it is particularly important in inhibiting inflammation and anti-oxidative stress. In addition to up-regulating the Nrf2 gene and increasing the expression of Nrf2, tBHQ’s role as an agonist of Nrf2 also allows it to block the activity of NF-κB and pro-inflammatory factors while inducing the production of anti-inflammatory proteins. Although the antioxidant mechanism of tBHQ is not completely clear, it can also exert anti-oxidative stress through Nrf2. According to studies, tBHQ can prevent neurotoxicity brought on by oxidative stress by activating the Nrf2-ARE and Keap1-Nrf2-ARE signaling pathways [164, 165], regulating NADPH oxidase system, regulating the activation of astrocytes and regulating GSH pathway [166]. In addition, tBHQ effectively prevents the production of related oxidation products, increases the level of antioxidant substances, and has a protective effect on the oxidative damage generated by the body, and at the same time promotes the recovery of the anti-oxidative mechanism of the damaged body. The preceding sections of this research go into great length into the neuroprotective mechanisms of tBHQ against AD, stroke, depression, PD and other brain diseases; they are summarized in Table 1.

Table 1 A list of neuroprotective effects of tBHQ
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In-depth study on tBHQ has drawn a lot of attention to its safety, even though certain research reports have indicated that tBHQ has a great deal of potential in the treatment of brain diseases [167]. Although tBHQ is frequently utilized as an antioxidant [168], researches have revealed that it also has certain harmful and carcinogenic properties [169,170,171]. The ability of tBHQ to generate ROS during the redox cycle can lead to cytotoxicity at high concentrations, which is strongly tied to this ability [172]. High-dose tBHQ can promote apoptosis and carcinogenicity in food additives, which slows the rate of growth of normal cells by causing apoptosis through chromatin and DNA fragmentation and causes cytotoxicity in a dose- and time-dependent manner [173]. Under in vitro conditions, the threshold concentration of tBHQ (30 M or less) induction of possible adverse effects is 30 M, and the range of tBHQ concentrations from beneficial to toxic may be 10 to 30 M, and tBHQ exhibits antioxidant effects below the concentration that causes adverse cellular reactions, so the blood concentration of tBHQ should not exceed 1.66 mg/L [174]. What is even more surprising is that studies have shown that a new type of antioxidant and prebiotic material can inhibit the toxicity of tBHQ by grafting tBHQ onto chitosan and further cross-linking to agavin, and the experimental results of acute oral toxicity in mice show that edible synthetic materials do not have adverse short-term effects [175]. This positive research data offers a point of reference and a specific research and development path for how to decrease the toxicity of tBHQ and enhance the safe use of clinical in the future.

As a result, even though tBHQ’s application has some flaws, this does not diminish the drug’s effectiveness. On the contrary, by examining its toxicity, tBHQ offers a safety assurance for the use of medications and paves the way for new avenues of investigation into ways to lessen tBHQ’s toxicity in upcoming research projects.