Introduction

Stroke is a major cause of death and disability in the world. Epidemiological studies have indicate that 80% of stroke cases are cerebral stroke [1]. The goal of treatment in ischemic stroke is to repair damaged tissues by restoring blood flow (reperfusion). Although reperfusion is a signal for the termination of hypoxia, it may subsequently increase cell death and damage [2]. Indeed, stroke can lead to cognitive and memory impairment, motor dysfunctions and, ultimately, dementia and neuronal death. Several signaling mechanisms are involved in the pathophysiology of ischemia-reperfusion injury (I/R injury) including inflammation, oxidative stress, disruption of the blood-brain barrier (BBB), mitochondria-mediated mechanisms, and leukocyte infiltration [3,4,5,6]. Innate and adaptive immune systems as well as the platelets, complement system and coagulation factors are also involved in I/R injury. After activation of these systems, necrosis and apoptosis occur via a number of mechanisms that ultimately lead to cell death. These processes stimulate the inflammatory system and lead to further release of nucleotides which make phagocytosis progress and ultimately worsen reperfusion injury [7, 8].

Several lines of experimental evidence have shown that phytocompounds such as crocin [9], carvacrol [10], thymoquinone [11], and curcumin [12] as well as different plants such as Artemisia absinthium, Ocimum basilicum, Ocimum sanctum, Ginkgo biloba, Gastrodia elata, Camellia sinensis, Olea europaea, Oleaceae europaea, and Lavandula officinalis have the potential to be efficacious in the treatment of stroke because of their antioxidant, free radical-scavenging, anti-thrombotic, anti-apoptotic, and neuroprotective properties [13].

Previous investigations have indicated that one of the compounds that can be effective in the treatment of stroke is curcumin. Curcumin is a yellow polyphenolic compound derived from turmeric. Previous reports have proposed that curcumin can be used as a potential drug for the treatment of many diseases such as cancer [14,15,16,17,18,19], diabetes [20, 21], cardiovascular [22,23,24,25,26,27], arthritic [28,29,30], psychological [31, 32], hepatic [33,34,35,36], pulmonary [37,38,39], and neurodegenerative disorders [40]. Most of these therapeutic effects have been attributed to the anti-inflammatory [29, 41, 42], antioxidant [43], and immunomodulatory [44,45,46,47] properties of curcumin. One of the beneficial features of curcumin is that despite its daily and long-term use in Asian countries, toxicity has not been reported [48, 49]. Several studies on the protective effects of curcumin have been presented in I/R experimental models [50,51,52]. For example, it has been shown that administration of curcumin prevents the negative effects of stroke on biochemical parameters, neurological scores, apoptosis, and subsequently infarct volume, edema, and hemorrhage in rats [53,54,55]. The aim of the present review was to explore these protective effects of curcumin against I/R injury in the nervous system.

I/R Injury in the Nervous System

Brain ischemia is caused when brain arteries are blocked acutely and cannot be recovered in a short time [56]. It has been shown that brain tissue and spinal cord are more sensitive to ischemia compared with other tissue such as the heart and kidney. In this regard, the blockage of blood flow to the brain for only 5 min can lead to the death of neurons, while cell death in cardiac or kidney tissues occurs after 20–40 min of ischemia [57, 58]. Ischemia-reperfusion (I/R) is the restoration of blood supply to an organ with seriously decreased or entirely stopped blood flow. Reperfusion is the main treatment for acute stroke and, at the same time, it can also worsen tissue damage and limit the recovery of function [8, 59]. Reperfusion may occur spontaneously after a stroke or it can also be achieved by thrombolytic therapy or endovascular therapy [60]. It has been shown in previous studies [61,62,63] that while reperfusion may improve complications in some cases, it may worsen brain injury in others. It has been indicated that the mechanisms underlying I/R injury include leukocyte infiltration, platelet activation, oxidative stress, complement activation, mitochondria-mediated mechanisms, disruption of the BBB, and ultimately post-ischemic hyperperfusion leading to edema or hemorrhagic transformation (HT) in the brain and spinal cord (Fig. 1) [6, 58, 64]. Leucocyte infiltration plays the main role in initiating the inflammatory process of cerebral ischemia-reperfusion injury. During reperfusion, chemical signals trigger binding of leukocytes to endothelial cells, followed by the production of neutrophil-derived oxidants and matrix metallo-proteinases that impair BBB [65]. It has been shown that after reperfusion platelets are activated and produce oxygen radicals and release pro-inflammatory factors such as platelet-derived growth factor, thromboxane A2, arachidonic acid metabolites, platelet factor 4, and serotonin [66].

Fig. 1
figure 1

Schematic diagram showing the various mechanisms of ischemia-reperfusion injury. The mechanisms of ischemia-reperfusion injury involves leukocyte infiltration, platelet activation, oxidative stress, complement activation, mitochondrial-mediated mechanisms, disruption of the BBB, and eventually post-ischemic hyperperfusion leading to edema or hemorrhagic transformation

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Oxidative stress also plays an important role in the pathogenesis of cerebral I/R injury. Oxidative stress occurs when the reactive oxygen species (ROS) surpass the antioxidant capacity of a cell or tissue. Prior studies have shown that production of ROS is increased after cerebral I/R injury, and these species can damage nearly all cellular components such as membrane lipids, proteins, and nucleic acids [67,68,69]. In I/R, due to increased amounts of free radicals, and deterioration and inactivation of antioxidant enzymes, defensive mechanisms are not enough to protect the tissue. Ischemia causes cell death through deprivation of oxygen supply, cell energy evacuation, and accumulation of toxic metabolites in the tissue. In contrast, reperfusion causes more tissue damage than that caused by ischemia [70, 71]. Cell energy evacuation causes inhibition of the Na+, K+-ATPase pump in the cell membrane. Consequently, intracellular Ca2+ ion concentration increases and activates several Ca2+-dependent enzymes like phospholipases, proteases, and endonucleases which may be involved in the production of ROS [72, 73]. Xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase are the main sources of ROS involved in reperfusion-induced oxidative stress.

Nitric oxide (NO) and superoxide anion (O2−) are generated in the brain during I/R via Nox and neuronal nitric oxide synthase (nNOS) activity, respectively. Peroxynitrite (ONOO−) produced by the interaction between NO and O2−. ONOO− is a potent oxidative radical that causes protein nitration and impairment. .OH, another oxidant, which is produced from H2O2, causes lipid peroxidation and protein, DNA and RNA oxidation, and subsequently cell death. Small amounts of these oxidants as signaling molecules are needed for the body but their increase in I/R injury leads to dysfunction [74,75,76].

The complement system is another main cause of I/R injury. It is a part of the innate immune system and consists of numerous cascades which are involved in the onset of inflammation induced by pathogens and therefore neuronal cell death. The complement system is implicated in I/R injury via different pathways including the antibody-dependent classical pathway, the lectin pathway or the alternative pathway, which are started by C1q, MBL/ficolins/collectin-11, and C3b, respectively. All of these pathways may cause the activation and cleavage of C3 into C3a and C3b. Finally, a complex called membrane attack complex (MAC) is formed through the activity of inflammatory mediators (anaphylatoxin C5a, distal complement component C5b-9), which cause various impairments including increased cell membrane permeability by formation of transmembrane channels, recruitment of leukocytes to the reperfused tissue, and induction of endothelial expression of monocyte chemo-attractant protein-1 (MCP-1), which has a main role in inflammation in the central nervous system (CNS) [77, 78].

Mitochondrial mechanisms play an important role in mediating cerebral I/R injury in several ways such as ROS generation, apoptosis, and necrosis [67, 79]. Studies have shown that disruption of BBB occurs in cerebral reperfusion injury and this leads to edema and hemorrhagic transformation following hyperperfusion [80, 81]. Within the CNS, astrocytes are fundamental for processes such as the development and maintenance of the BBB, promotion of neurovascular coupling, recruitment of cells through the release of chemokines, release of gliotransmitters, regulation of calcium levels, release and transport of glutamate by calcium signaling through the GLAST and EAAT transporters, maintenance of brain general metabolism, control of cerebral pH, uptake of GABA (γ-aminobutyric acid) by specific transporters, and the production of antioxidant enzymes [3, 5, 82,83,84,85]. During I/R, astrocyte undergoes morphological changes and turn into a reactive-like hyperplasic state. This may result in the formation of a glial scar [86] and secretion of various inflammatory and damaging molecules that may worsen the still intact nervous tissue and expands the penumbra towards the healthy brain tissue. It is important to note that neurons are more susceptible to I/R injury than astrocytes, since these cells have a lower antioxidant capacity and require a great deal of metabolic coupling with astrocytes to combat oxidative stress [85], especially during an I/R event. Previous studies have shown mitochondrial dysfunction in astrocytes upon glucose deprivation in an in vitro model of ischemia. The reported mitochondrial dysfunction was reflected by reduced mitochondrial mass, increased oxidative stress, and reduced mitochondrial membrane potential [87, 88]. On the contrary, other studies pointed that improving mitochondrial function in astrocytes by targeting neuroglobin, a protein of globin family, aimed at protecting neurons is an important experimental strategy to counteract inflammatory stimuli [89,90,91].

Potential Therapeutic Strategies in Stroke: Curcumin

Curcuma longa L., generally known as turmeric, is a native plant of South Asia, India, and Indonesia and is mainly grown in South India [92]. It belongs to the ginger family. The main bioactive constituents of turmeric are curcuminoids that include demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), and curcumin. Curcumin is the predominant curcuminoid which can constitute as high as 80% of total curcuminoids in turmeric [93, 94]. Commercial extracts of curcumin are a mixture of all three mentioned curcuminoids [95]. Curcumin is used as a spice, food preservative, and coloring agent while having a long history of use in the Ayurvedic medicine for the treatment of various diseases [96]. Vogel and Pelletier for the first time isolated impure form of curcumin in 1815, and its chemical structure was discovered by Milobedzka and Lampe in 1910 as diferuloylmethane or 1,6-heptadiene-3,5-dione-1,7-bis (4-hydroxy-3-methoxyphenyl)-(1E, 6E) (Fig. 2) [97]. Curcumin has a light yellow color and is used as a natural coloring agent in the food industry (the code for this usage is E100) [98]. Because of low oral absorption of curcumin and its rapid metabolism in the liver, consumption of curcumin with piperine has been suggested as an efficient strategy to increase the bioavailability of curcumin [99, 100]. Also, micellar surfactants and phospholipid complexed have been shown to increase the absorption of curcumin by significant orders [101, 102].

Fig. 2
figure 2

Chemical structure of curcumin

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Curcumin is a pleiotropic molecule and has numerous molecular and cellular targets by which it can exert its biological effects. These targets include growth factor receptors, transcription factors, protein kinases, adhesion molecules, apoptosis-related proteins, inflammatory cytokines, enzymes like ATPase, cyclooxygenase-2 (COX-2), and matrix metallo-proteinases [103]. Spectroscopic results showed that curcumin binds to human serum albumin with a strong affinity [104]. Furthermore, curcumin has been reported to possess wide range of biological activities including antioxidant [105], antivenom [106], antimicrobial [107], anti-HIV [108], anti-tumor [109], anti-inflammatory [110], antiprotozoal [111], nephroprotective [112], and antirheumatic [113] activities plus therapeutic effects against myocardial infarction [114], skin diseases [115], and cystic fibrosis [116].

Neuroprotective Effects of Curcumin

It has been shown that curcumin has protective effects against neuronal damage risk factors like inflammation [117], free radicals [118], ischemia [119], amyloid [120], and apoptosis [121]. Previous research has also shown that curcumin regulates adhesion molecules, cytokines, protein kinases, and enzymes that are related to inflammation [122, 123]. Studies have revealed that curcumin can improve many neurological disorders such as anxiety, depression, neuronal injury, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s pathology, head trauma, and stroke [124]. Moreover, curcumin has been proposed as a potential candidate to increase the cholinergic activity of neurons in streptozotocin-induced dementia in rats [125].

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for development and protection of the brain. DHA deficiency is related to some neurological disorder like anxiety [126, 127]. Wu et al. showed that curcumin raises the levels of enzymes such as FADS2 and elongase 2 which are involved in the synthesis of DHA in both liver and brain tissues, and increases the production of DHA [128]. Numerous studies reported that curcumin protects cerebellar granule cells, hippocampal cells, and retinal cells against glutamate excitotoxicity [129, 130]. One prior study determined that curcumin can improve cognitive impairment by acting through the brain-derived neurotrophic factor (BDNF) system in a rat traumatic brain injury (TBI) model. In this regard, curcumin may increase BDNF protein levels, which then activate TrkB phosphorylation and hence promote neuronal survival [131]. Furthermore, it has been suggested that curcumin promotes neuronal damage induced by chronic stress via upregulation of serotonin receptor 1A (5-HT1A receptor) mRNA and BDNF [132]. Curcumin has beneficial actions on seizures via its function as a free radical scavenger and an antioxidant [133]. For example, Ono et al. reported that curcumin treatment significantly increased glutathione (GSH) levels in the brain tissue of epileptic mice. GSH is one of the free radical scavengers which protect cells against oxidative damage [134].

Curcumin also regulates monoamine neurotransmission and oxidation in the brain, neuroinflammation, and hypothalamus–pituitary–adrenal (HPA) axis and, through these effects, it can act as an antidepressant [135]. Recently, a randomized double-blind study on 123 subjects with depression showed that curcumin supplementation for 12 weeks could reduce the symptoms of depression in comparison with the control group [136]. It is also hypothesized that neuroprotection of curcumin might be mediated via BDNF/tyrosine kinase B (TrkB)MAPK/PI-3K-cyclic AMP response element binding protein (CREB) signaling pathway. In this sense, Wang et al. confirmed the effect of curcumin on the activation of this signaling cascade and showed that this compound induced the viability of cultured rodent cortical neurons [137].

It is proven that curcumin has anti-inflammatory, antioxidant, and anti-amyloid activity; therefore, it can be useful in the treatment and/or prevention of Alzheimer’s disease (AD) as shown previously [138]. Previous works have indicated that curcumin inhibits lipoxygenase and COX-2, two enzymes that are responsible for the synthesis of the pro-inflammatory leukotrienes, prostaglandins, and thromboxanes [139]. Another factor that is involved in the pathophysiology of AD is cholesterol, which is involved in β-amyloid (Aβ) deposition. It has been shown that the use of curcuminoids (500 mg/day) for 7 days decreased the levels of serum cholesterol and lipid peroxides in healthy volunteers [140]. Furthermore, Yang et al. reported that in AD mice model, administration of curcumin decreased the level of Aβ by 40% in comparison with control mice [141]. Several studies support the clinical application of curcumin in Parkinson’s disease (PD) [142, 143]. Aggregation of oxidized DNA is involved in the pathophysiology of PD [144] and transition metal ions such as Fe (II/III) and Cu (II) inhibit DNA repair enzymes [145]. As such, curcumin can reverse such inhibition of DNA repair enzymes both in vitro and in vivo [143]. Furthermore, the antioxidant activity of curcumin protects substantia nigra neurons, improves striatal dopamine levels and chelates Fe2+ in the 6-OHDA rat model of PD [142].

Protective Effects of Curcumin Against Neurological I/R Injury

Curcumin has many protective effects against neurological IRI in brain and spinal cord. In this section, we will address some signaling mechanisms that are sought to be protective upon treatment with curcumin.

Effect of Curcumin Against I/R Injury in Brain

Administration of curcumin (300 mg/kg ip) prior to reperfusion in rat middle cerebral artery occlusion (MCAO) model reduced infarct size and brain edema at 24 h, improved microvascular hemodynamics, and restored blood velocity and shear rate. Treatment with curcumin also improved neurological function and subsequently neurological scores at 24 h. The main protective effect of curcumin was recognized in the striatum, where the highest reduction in infarct size and brain edema was observed [146]. In another study, significant impairment of the motor performance was seen in the embolic occlusion of the MCAO model of rats [147]. Increased neurological defects and reduced dwell-time on the rotarod occurred in animals which may be due to neural damage in the cerebellum that regulates motor coordination [148, 149]. Results from another study showed that occlusion-induced ischemia caused severe neurobehavioral deficits in animals and the defects were significantly smaller in curcumin-treated animals at 3, 7, and 12 day after stroke. It has been shown that curcumin did not improve neurobehavioral recovery at 1 day after stroke, possibly because of the dose and administration route used. Furthermore, curcumin treatment increases BrdU (marker of migrating cells) labeled cells 12 days after MCAO, suggesting rapid migration of new cells into the ischemic region and indicating DNA replication [150]. Investigators suggest that 12 day-period is suitable for observing a major part of neurogenesis and migration that occurs after stroke in rats [151]. In a recent study conducted by Altinay et al., cellular damage indices such as shrunken cytoplasm, atrophic neurons, and damaged nuclei were present in hematoxylin and eosin-stained forebrain sections of stroke animals and these parameters were found to be reduced upon administration of curcumin [53]. It has also been demonstrated that astrogliosis plays a main role in the pathology of cerebral ischemia [5, 152, 153]. In this regard, Kalani et al. showed that curcumin-loaded embryonic stem cell exosomes (MESC-exocur) normalized astrogliosis and improved neuronal survival following I/R injury in mice. Moreover, tight junction protein loss induced by IRI was alleviated in mice treated with MESC-exocur [54]. Major findings from another study indicated that a single-dose administration of FeTPPs, curcumin, or minocycline improved 24-h post-stroke bleeding at the reperfusion site in diabetic animals and this was associated with reduced matrix metallo-proteinases-9 activity [55]. Dietary supplementation with curcumin (2.0 g/kg) for 2 months reduced neuronal death in the hippocampal CA1 region in an experimental I/R-induced brain ischemia model [154]. Furthermore, reduction in locomotor count and decrease in grip strength were improved in middle cerebral artery (MCA)-occluded rats following intranasal delivery of curcumin, DMC, and BDMC [155]. A summary of protective effects of curcumin in I/R injury is displayed in Table 1.

Table 1 Summary of studies reporting protective effects of curcumin against ischemia-reperfusion injury in the nervous system
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Effect of Curcumin Against I/R Injury in Spinal Cord

Lin et al. showed that curcumin strongly reduced RANTES production in reactive astrocytes both in vitro and in vivo, and this may contribute to its neuroprotection during spinal cord ischemia. The authors also indicated that curcumin inhibited neuronal loss and astrocyte activation, and improved neurological deficits [160]. Similarly, administration of curcumin significantly decreased axonal damage, neuronal degeneration, and glial cell infiltration parameters in I/R-induced spinal cord ischemia in rabbits [158]. In a recent study conducted by Gokce et al., rats from the I/R injury group that received saline treatment exhibited histological changes related to ischemic injury including widespread edema, diffused hemorrhage and congestion and neuronal damage, as evidenced by pyknosis, intense axonal swelling, loss of cytoplasmic features, and cytoplasmic eosinophilia. On the contrary, curcumin (200 mg/kg for 7 days before induction of I/R injury) markedly reduced these pathological changes in rats (153, 154), suggesting that curcumin protects spinal cord tissue in these animals against injury. Moreover, the mean number of normal motor neurons in the anterior spinal cords decreased in rats sufferring from spinal cord IRI while curcumin-treated rats had significantly greater numbers of normal motor neurons than rats sufferring from spinal cord IRI (153, 154). Furthermore, the authors also showed that ultrastructural abnormalities in white and gray matter induced by I/R injury such as severe interruptions and separations in small, medium, and large myelinated axons, separations and interruptions in myelin configuration, swollen neuronal mitochondria, and perineural edema were less severe in curcumin-treated animals. The severity of hind-limb motor dysfunction after spinal cord I/R injury in rats was determined using the Basso, Beattie, and Bresnahan grading scale. Animals in the I/R injury group showed severe neurological deficits and decreased score, while treatment with curcumin increased the abovementioned score [58, 157, 159].

Molecular Mechanisms Underlying Protective Effects of Curcumin Against I/R Injury

There are several molecular mechanisemes underlying protective effects of curcumin against I/R injury as described in details below.

The Effect of Curcumin on Inflammation and Oxidative Stress

In the early stages of I/R injury, inflammation accelerates the process of injury and determines the severity of cerebral damage [161]. Oxidative stress and overproduction of reactive oxygen species (ROS) is a constant feature and an important mechanism of I/R injury [162]. Althogh ROS play several key roles in normal physiology, excessive production of these species may contribute to the pathophysiology of I/R injury as the brain tissue is very sensitive to oxidative damage. Previous studies have identified that administration of curcumin improved I/R injury due to its antioxidant effects [163,164,165]. Morover, significantly prevented cerebral I/R injury (CIRI) via ameliorating oxidative damage [155, 166]. Possible mechanisms of the protective effect of curcumin against oxidative stress include decreasing lipid peroxidation (a sensitive marker of oxidative damage), enhancement of protein synthesis, scavenging of free radicals, increasing glutathione (GSH) content, and preservation of cell membrane integrity [155, 166, 167]. Jia et al. reported that peroxiredoxin 6 (PRDX6) upregulation by curcumin treatment attenuated ischemic oxidative damage through transcription factor specific protein 1 (SP1) induction in rats after stroke [166]. Another study showed that curcumin induced the expression of thioredoxin (an antioxidant protein) and protected neurons from oxygen-glucose deprivation-induced death in an in vitro model of I/R [168]. Among potential mediators of ischemic brain pathology are inflammatory cytokines such as IL-1β, IL-6, TNF-α, prostaglandin E2 (PGE2), NO, COX-2 and inducible nitric oxide synthase (iNOS). In this sense, curcumin protects the brain from ischemia via suppression of inflammatory cytokines like TNF-α and IL-6 [169].

Anti-apoptotic Effect of Curcumin

Apoptosis is one of the major pathways that can lead to the process of cell death after I/R injury [153]. Curcumin contributes to neuronal protection possibly through anti-apoptotic mechanisms [170]. Oxidative stress affects the mitochondrial outer membrane and, as a consequence, Bax moves from the cytosol to mitochondria and cytochrome c is released into cytosol, and this translocation is regulated by B-cell lymphoma 2 (Bcl-2) protein. Release of cytochrome c into cytosol leads to the formation of apoptosome, a complex composed of apoptotic-protease activating factor-1, procaspase-9, and ATP. Formation of apoptosome leads to the activation of procaspase-9 and, consequently, activation of procaspase-3. Eventually, caspase-3 leads to DNA fragmentation [171,172,173]. Interestingly, curcumin increased the levels of anti-apoptotic Bcl-2 protein in mitochondria and reduced subsequent translocation of cytochrome c into cytosol, therefore attenuating the downstream caspase activation (Fig. 3) [170]. It has been suggested that the mitochondrial pathway is an important target of curcumin. Ischemia-induced mitochondrial dysfunction in neurons can be detected by measuring the release of cytochrome c from mitochondria. Qun Wang et al. demonstrated that administration of curcumin completely suppressed the ischemia-induced release of cytochrome c [154]. Another mechanism through which curcumin prevents cerebral I/R injury is increasing silent information regulator 1 (Sirt1) expression, a key neuroprotective molecule that is involved in protection against cerebral I/R. In this regard, activation of Sirt1 leads to the deacetylation of p53 and attenuation of apoptosis in the ischemic brain [169].

Fig. 3
figure 3

The propose mechanism of anti-apoptotic effect of curcumin. Oxidative stress affects the mitochondrial outer membrane, Bax moves from the cytosol to mitochondria, and cytochrome c is released into cytosol. This translocation is regulated by Bcl-2 proteins. Release of cytochrome c into cytosol leads to the formation of a complex composed of apoptotic-protease activating factor-1, procaspase-9, and ATP (apoptosome), and this leads to the activation of procaspase-9 and then procaspase-3. Curcumin increases the levels of anti-apoptotic Bcl-2 protein in mitochondria and reduces the translocation of cytochrome c into cytosol, thereby exerting its anti-apoptotic effects

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The Effect of Curcumin on Mitochondrial Biogenesis

It has been documented that mitochondrial number/mass, mitochondrial biogenesis, and the mitochondrial uncoupling protein 2 (UCP2) (an inner mitochondrial membrane anion carrier protein implicated in protecting neurons against cerebral ischemia injury), were significantly downregulated in rats with I/R injury, and these changes were reversed by curcumin pretreatment. It has also been demonstrated that mitochondrial biogenesis was increased in the MCAO reperfusion model of rats upon treatment with curcumin [174].

The Effect of Curcumin on Endoplasmic Reticulum

It has been suggested that in response to CIRI, numerous predisposing factors of endoplasmic reticulum stress (ERS) are activated in neurons including depletion of ER Ca2+, aggregation of proteins, decreased protein degradation, and accumulation of lipid peroxidation products in ER and Golgi structures [175]. ERS may induce pro-apoptotic processes and lead to apoptosis [176, 177]. DNA damage-inducible 153 (GADD153) and caspase-12 are among the main drivers of ERS-mediated apoptosis [178]. GADD153 is a signaling molecule which is involved in the development of apoptosis through several pathways such as affecting intracellular Ca2+ metabolism and downregulating Bcl-2 [178,179,180]. Caspase-12 is another important factor in ERS-mediated apoptosis. Caspase-12 is released from the ER during ERS and subsequently activates the caspase cascade and apoptosis. The precise mechanism of curcumin’s effect on ERS inhibition is still unknown, and this may be related to decreasing the activity of nuclear factor (NF)-κB, increasing the expression of PRDX6 or activating the sirtuin type 1 pathway. It has been shown that curcumin can improve ERS via decreasing the expression of the GADD153 and caspase-12, thereby exhibiting protective effects against CIRI in rats [178].

The Effect of Curcumin on Blood-Brain Barrier Integrity

After stroke, there is an increase in the permeability of the vessels and this causes BBB disruption and vasogenic edema. Previous studies have indicated that NO contributes to ischemia-induced disruption of BBB. NO is a free radical which is involved in the pathogenesis of cerebral ischemia due to its neurotoxic effects. NO reacts with O2− quickly and produces ONOO− [181,182,183]. ONOO− is a toxic anion that produces hydroxyl radicals. These radicals impair key enzymes of the tricarboxylic acid cycle, mitochondrial respiratory chain, mitochondrial Ca2+ metabolism and induce DNA damage, leading to endothelial injury. Jiang et al. showed that curcumin prevented ONOO−−mediated BBB disruption and improved cerebral I/R injury (179). The authors hypothesized that curcumin acts via reducing ONOO− production by inhibiting iNOS expression in astrocytes or by a direct route preventing cerebral capillaries’ endothelial cell injury induced by ONOO− [183, 184]. In general, curcumin has been shown to prevent I\R-induced disruption of BBB via numerous mechanisms such as inhibiting the cytotoxicity of SIN-1 on BCECs, reducing water content of the brain in ipsilateral hemisphere, preventing the absorbance of Evans blue dye after focal cerebral ischemia, inhibiting iNOS expression in cultured astrocytes, and blocking NF-κB activation [183,184,185].

Conclusions

In the present review, we discussed the neuroprotective effects of curcumin against I/R injury. Accumulating evidence has shown that curcumin ameliorate I/R injury through different mechanisms such as mitigation of inflammation, apoptosis and ERS, and enhancement of mitochondrial biogenesis. Nevertheless, prospective studies are needed to further elucidate how curcumin could exert its protective effects against cerebral I/R injury and possible therapeutic applications thereof. In particular, supportive evidence from randomized controlled trials would be crucial.