curcumin and Brain-Injuries--Traumatic

Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR's beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer's and Parkinson's diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions.

Topics: Amyloid beta-Peptides; Animals; Brain; Brain Injuries, Traumatic; Curcumin; Phosphatidylinositol 3-Kinases

Neuroinflammation is a key pathophysiological mechanism implicated in the neurodegenerative condition. One such condition implicating neuroinflammation is traumatic brain injury (TBI). Over the past decades, various alternative natural compounds, such as curcumin, have been investigated as novel therapeutic options to mitigate the pathophysiological pathways and clinical sequelae involved in TBI. As the main component of turmeric (Curcuma longa), curcumin has a broad range of clinical properties due to its considerable antioxidative and anti-inflammatory actions. This review discusses the pleiotropic mechanisms, the side effects, curcumin's delivery to the central nervous system (CNS), and its immunomodulatory and protective effects on TBI. Clinical trials, in vivo, and in vitro studies were extracted from different scientific databases, including PubMed, Scopus, and Google Scholar, to assess the effects of curcumin or its derivatives in TBI. Findings reveal that curcumin exhibited some protective effects on TBI via modulation of cell signaling pathways including toll-like receptor-4 (TLR-4), nuclear factor kappa B (NF-κB), and Nod-like receptor family proteins (NLRPs). Moreover, curcumin upregulates the brain-derived Neurotrophic Factor/Tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), nuclear factor erythroid 2-related factor 2 (Nrf2), which have crucial functions in modulation of TBI pathophysiological-mediated pathways. Curcumin displays beneficial immunomodulatory functions and protective capacities in different TBI models, although more clinical experiments are required to clarify curcumin's precise mechanisms and function in TBI.

Topics: Brain Injuries, Traumatic; Curcumin; Humans; NF-kappa B; Phosphatidylinositol 3-Kinases; Signal Transduction

Autophagy is a highly conserved cellular degradation process involving lysosomal degradation for the turnover of proteins, protein complexes, and organelles. Defects in autophagy produces impaired intercellular communication and have subsequently been shown to be associated with pathological conditions, including neurodegenerative diseases. Curcumin is a polyphenol found in the rhizome of Curcuma longa, which has been shown to exert health benefits, such as antimicrobial, antioxidant, anti-inflammatory, and anticancer effects. There is increasing evidence in the literature revealing that autophagy modulation may provide neuroprotective effects. In light of this, our current review aims to address recent advances in the neuroprotective role of curcumin-induced autophagy modulation, specifically with a particular focus on its effects in Alexander disease, Alzheimer's disease, ischemia stroke, traumatic brain injury, and Parkinson's disease.

Topics: Autophagy; Biological Availability; Brain Injuries, Traumatic; Brain Neoplasms; Curcumin; Diabetes Mellitus; Humans; Neurodegenerative Diseases; Neuroprotective Agents

Traumatic Brain Injury (TBI) is one of the main causes of mortality and morbidity worldwide with no suitable treatment. The present study was designed to review the present literature about the protective effects of curcumin and the underlying mechanism against TBI. All published English language papers from beginning to 2019 were selected in this study. The findings indicate that curcumin may be effective against TBI outcomes by modulating the molecular signaling pathways involved in oxidative stress, inflammation, apoptosis, and autophagy. However, more experimental studies should be done to identify all mechanisms involved in the pathogenesis of TBI. Patents for Curcumin and chronic inflammation and traumatic brain injury management (WO2017097805A1 and US9101580B2) were published. In conclusion, the present study confirmed the potential therapeutic impact of curcumin for treating TBI.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Brain; Brain Injuries, Traumatic; Curcuma; Curcumin; Humans; Inflammation; Oxidative Stress; Patents as Topic; Phytotherapy; Plant Extracts

Neuroinflammation and oxidative stress after traumatic brain injury (TBI) can further lead to neuronal apoptosis, which plays a crucial role in the process of neuron death. Curcumin, which is derived from the rhizome of the Curcuma longa plant, has multiple pharmacological effects.. The objective of this study was to investigate whether curcumin treatment has neuroprotective effects after TBI, and to elucidate the underlying mechanism.. A total of 124 mice were randomly divided into 4 groups: Sham group, TBI group, TBI+Vehicle group, and TBI+Curcumin group. The TBI mice model used in this study was constructed with TBI device induced by compressed gas, and 50 mg/kg curcumin was injected intraperitoneally 15 minutes after TBI. Then, the blood-brain barrier permeability, cerebral edema, oxidative stress, inflammation, apoptosis-related protein, and behavioral tests of neurological function were utilized to evaluate the protective effect of curcumin after TBI.. Curcumin treatment markedly alleviated post-trauma cerebral edema and blood-brain barrier integrity, and suppressed neuronal apoptosis, reduced mitochondrial injury and the expression of apoptosis-related proteins. Moreover, curcumin also attenuates TBI-induced inflammatory response and oxidative stress in brain tissue and improves cognitive dysfunction after TBI.. These data provide substantial evidence that curcumin has neuroprotective effects in animal TBI models, possibly through the inhibition of inflammatory response and oxidative stress.

Topics: Animals; Brain Edema; Brain Injuries, Traumatic; Curcumin; Disease Models, Animal; Mice; Neuroinflammatory Diseases; Neuroprotective Agents; Oxidative Stress

Traumatic brain injury (TBI) is a common disease worldwide with a high mortality and disability rate and is closely related to the inflammatory response. However, the molecular mechanisms during the pathophysiological responses are not completely understood. This study was conducted to investigate the protective effect of curcumin on TBI and the molecular mechanisms of the p38/MAPK signal pathway. We found that curcumin remarkably ameliorated secondary brain injury after TBI, including effects on the neurological severity score and inflammation. After injection of curcumin, the neurological function score of mice decreased significantly. Curcumin exhibited antiinflammatory pharmacological effects, as reflected by inhibition of inflammatory factors (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α). Additionally, curcumin notably reduced the expression of p-p38 according to western blotting and immunohistochemical analyses. In conclusion, curcumin remarkably alleviated posttraumatic inflammation and thus shows potential for treating inflammation associated with TBI.

Topics: Animals; Brain Injuries, Traumatic; Curcumin; MAP Kinase Signaling System; Mice; p38 Mitogen-Activated Protein Kinases; Signal Transduction

Despite a great amount of effort, there is still a need for reliable treatments of traumatic brain injury (TBI). Recently, stem cell therapy has emerged as a new avenue to address neuronal regeneration after TBI. However, the environment of TBI lesions exerts negative effects on the stem cells efficacy. Therefore, to maximize the beneficial effects of stem cells in the course of TBI, we evaluated the effect of human neural stem/progenitor cells (hNS/PCs) and curcumin-loaded niosome nanoparticles (CM-NPs) on behavioral changes, brain edema, gliosis, and inflammatory responses in a rat model of TBI. After TBI, hNS/PCs were transplanted within the injury site and CM-NPs were orally administered for 10 days. Finally, the effect of combination therapy was compared to several control groups. Our results indicated a significant improvement of general locomotor activity in the hNS/PCs + CM-NPs treatment group compared to the control groups. We also observed a significant improvement in brain edema in the hNS/PCs + CM-NPs treatment group compared to the other groups. Furthermore, a significant decrease in astrogliosis was seen in the combined treatment group. Moreover, TLR4-, NF-κB-, and TNF-α- positive cells were significantly decreased in hNS/PCs + CM-NPs group compared to the control groups. Taken together, this study indicated that combination therapy of stem cells with CM-NPs can be an effective therapy for TBI.

Topics: Animals; Brain Edema; Brain Injuries, Traumatic; Curcumin; Disease Models, Animal; Gliosis; Nanoparticles; Neural Stem Cells; Rats

Traumatic brain injury (TBI) affects approximately 50% of the world population at some point in their lifetime. To date, there are no effective treatments as most of the damage occurs due to secondary effects through a variety of pathophysiological pathways. The phytoceutical curcumin has been traditionally used as a natural remedy for numerous conditions including diabetes, inflammatory diseases, and neurological and neurodegenerative disorders. We have carried out a system pharmacology study to identify potential targets of a difluorinated curcumin analogue (CDF) that overlap with those involved in the pathophysiological mechanisms of TBI. This resulted in identification of 312 targets which are mostly involved in G protein-coupled receptor activity and cellular signalling. These include adrenergic, serotonergic, opioid and cannabinoid receptor families, which have been implicated in regulation of pain, inflammation, mood, learning and cognition pathways. We conclude that further studies should be performed to validate curcumin as a potential novel treatment to ameliorate the effects of TBI.

Topics: Brain Injuries, Traumatic; Curcumin; Inflammation; Network Pharmacology; Oxidative Stress; Protein Interaction Maps; Receptors, G-Protein-Coupled; Signal Transduction

Gas explosion (GE)-induced traumatic brain injury (TBI) can affect thyroid hormone (TH) homeostasis in miners. This study evaluated the effects of hepatic transthyretin and hypothalamic-pituitary-thyroid (HPT) axis on thyroids and explored the protective effect and mechanism of curcumin on GE-induced TBI. Thirty rats were randomly divided into three groups (10 per group): first group (control group)-rats received GE treatment once; second group (GE group)-rats received GE treatment (200 m from the source of the explosion once); third group (GE + Cur group)-rats received curcumin (Cur) by lavage at a dose of 100 mg/kg/day once every other day for 7 days after receiving GE. After GE, the pathological changes were analyzed by hemotoxylin and eosin staining, and the levels of serum reactive oxygen species (ROS), urine iodine (UI), THs, nuclear factor-kappa B (NF-κB), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and malondialdehyde (MDA) were analyzed using ELISA. Expression of proteins in the HPT axis of rats was examined by immunohistochemistry and Western blotting. We found that GE could induce pathologic changes in rat thyroid and liver. Serum levels of THs, NF-κB and serum redox state became unbalanced in rats after GE. GE could inhibit the biosynthesis and biotransformation of THs by affecting key HPT axis proteins. Additionally, GE reduced the level of hepatic transthyretin. Serum THs levels and thyroid sections were almost recovered to normal after curcumin treatment. The aforementioned key HPT axis proteins in the curcumin group showed opposite expression trends. In summary, GE affected THs balance while curcumin can protect against these injury effects by affecting TH biosynthesis, biotransformation, and transport, and inducing oxidative stress and inflammatory responses.

Topics: Animals; Brain Injuries, Traumatic; Curcumin; Eosine Yellowish-(YS); Explosions; Glutathione Peroxidase; Hematoxylin; Iodine; Male; Malondialdehyde; NF-kappa B; Oxidative Stress; Prealbumin; Rats; Reactive Oxygen Species; Superoxide Dismutase; Thyroid Gland; Thyroid Hormones

Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG-MnEMNPs-Cur, AMEC) mediate antioxidation and anti-neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep-2 functionalized and manganese doped eumelanin-like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T

Topics: Animals; Antioxidants; Brain; Brain Injuries, Traumatic; Curcumin; Disease Models, Animal; Manganese; Melanins; Mice; Mice, Inbred C57BL; Nanocomposites; Precision Medicine

Germacrone (GM) is a terpenoid compound which is reported to have anti-inflammatory and anti-oxidative effects. However, its role in treating traumatic brain injury (TBI) remains largely unknown.. Male C57BL/6 mice were divided into the following groups: control group, TBI group [controlled cortical impact (CCI) model], CCI + 5 mg/kg GM group, CCI + 10 mg/kg GM group and CCI + 20 mg/kg GM group. GM was administered via intraperitoneal injection. The neurological functions (including motor coordination, spatial learning and memory abilities) and brain edema were measured. Nissl staining was used to detect the neuronal apoptosis. Colorimetric assays and enzyme linked immunosorbent assay (ELISA) kits were used to determine the expression levels of oxidative stress markers including myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD), as well as the expressions of inflammatory markers, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Additionally, protein levels of Nrf2 and p-p65 were detected by Western blot assay.. GM significantly ameliorated motor dysfunction, spatial learning and memory deficits of the mice induced by TBI and it also reduced neuronal apoptosis and microglial activation in a dose-dependent manner. Besides, GM treatment reduced neuroinflammation and oxidative stress compared to those in the CCI group in a dose-dependent manner. Furthermore, GM up-regulated the expression of antioxidant protein Nrf2 and inhibited the expression of inflammatory response protein p-p65.. GM is a promising drug to improve the functional recovery after TBI via repressing neuroinflammation and oxidative stress.

Topics: Animals; Brain; Brain Edema; Brain Injuries, Traumatic; Curcuma; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Memory; Mice, Inbred C57BL; Microglia; Nervous System Diseases; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Phytotherapy; Plant Extracts; Recovery of Function; Sesquiterpenes, Germacrane; Spatial Learning

Cognitive decline is one of the most obvious symptoms of traumatic brain injury (TBI). Previous studies have demonstrated that cognitive decline is related to substantially increased neuroinflammation and decreased neurogenesis in the hippocampus in a rat model of TBI. Using this model, we explored the role of curcumin (Cur) in ameliorating TBI-impaired spatial memory because Cur has been shown to exhibit anti-chronic-neuroinflammatory, neurogenesis-promoting, and memory-improving properties. Animals received daily Cur or vehicle treatment for 28 days after TBI and also received 50-bromodeoxyuridine(BrdU) for the first 7 days of the treatment for assaying neurogenesis. An optimal Cur dose of 30 mg/kg, selected from a range of 10-50 mg/kg, was used for the present study. Neuroinflammation was evaluated by astrocyte hypertrophy, activated microglia, and inflammatory factors in the hippocampus. Behavioral water-maze studies were conducted for 5 days, starting at 35-day post-TBI. The tropomyosin receptor kinase B (Trkb) inhibitor, ANA-12, was used to test the role of the brain-derived neurotrophic factor (BDNF)/ TrkB/Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in regulating inflammation and neurogenesis in the hippocampus. Treatment with Cur ameliorated the spatial memory of TBI rats, reduced TBI-induced chronic inflammation, typified by diminished astrocyte hypertrophy, reduction in activated microglia, declined inflammatory factors, and increased neurogenesis in the hippocampus. We also found that BDNF/Trkb/PI3K/Akt signaling was involved in the effects of Cur in TBI rats. Thus, Cur treatment can ameliorate the spatial memory in a murine model of TBI, which may be attributable to decreased chronic neuroinflammation, increased hippocampal neurogenesis, and/or BDNF/Trkb/PI3K/Akt signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Injuries, Traumatic; Curcumin; Dose-Response Relationship, Drug; Hippocampus; Inflammation Mediators; Male; Maze Learning; Neurogenesis; Rats; Rats, Sprague-Dawley; Spatial Memory

Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide with no effective treatment. Curcumin has been shown to be beneficial for neuroprotection in vivo and in vitro, but the underlying mechanism remains unclear. This study determined whether the neuroprotective role of curcumin in mouse TBI is dependent on the NF-E2-related factor (Nrf2) pathway. The Feeney weight-drop contusion model was used to mimic TBI. Curcumin was administered intraperitoneally 15 min after TBI induction, and brains were collected at 24 h after TBI. The levels of Nrf2 and its downstream genes (Hmox-1, Nqo1, Gclm, and Gclc) were detected by Western blot and qRT-PCR at 24 h after TBI. In addition, edema, oxidative damage, cell apoptosis and inflammatory reactions were evaluated in wild type (WT) and Nrf2-knockout (Nrf2-KO) mice to explore the role of Nrf2 signaling after curcumin treatment. In wild type mice, curcumin treatment resulted in reduced ipsilateral cortex injury, neutrophil infiltration, and microglia activation, improving neuron survival against TBI-induced apoptosis and degeneration. These effects were accompanied by increased expression and nuclear translocation of Nrf2, and enhanced expression of antioxidant enzymes. However, Nrf2 deletion attenuated the neuroprotective effects of curcumin in Nrf2-KO mice after TBI. These findings demonstrated that curcumin effects on TBI are associated with the activation the Nrf2 pathway, providing novel insights into the neuroprotective role of Nrf2 and the potential therapeutic use of curcumin for TBI.

Topics: Animals; Antioxidants; Apoptosis; Brain; Brain Injuries, Traumatic; Curcumin; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction

Curcumin has been found to play the protective role in many neurological disorders, however, its roles and the underlying molecular mechanisms in traumatic brain injury (TBI) are not fully understood. The aim of this study was to investigate the potential neuroprotection of curcumin and the possible role of Nrf2-ARE pathway in the weight-drop model of TBI. The administration of curcumin (100 mg/kg, i.p.) significantly ameliorated secondary brain injury induced by TBI, such as brain water content, oxidative stress, neurological severity score, and neuronal apoptosis. Curcumin possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of cleaved caspase-3. Moreover, curcumin markedly enhanced the translocation of Nrf2 from the cytoplasm to the nucleus, proved by the results of western blot and immunofluorescence, subsequently increased the expression of downstream factors such as heme oxygenase 1 (HO1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) and prevented the decline of antioxidant enzyme activities. In conclusion, curcumin could increase the activities of antioxidant enzymes and attenuate brain injury in the model of TBI, possibly via the activation of the Nrf2-ARE pathway.

Topics: Animals; Apoptosis; Brain; Brain Injuries, Traumatic; Carboxylic Ester Hydrolases; Curcumin; Disease Models, Animal; Male; Mice, Inbred ICR; Neurons; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Random Allocation; Signal Transduction

The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood. This study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway.

Topics: Animals; Brain Injuries, Traumatic; Curcumin; Male; Neuroprotective Agents; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction

Tetrahydrocurcumin provides neuroprotection in multiple neurologic disorders by modulating oxidative stress, inflammatory responses, and autophagy. However, in traumatic brain injury (TBI), it is unclear whether a beneficial effect of tetrahydrocurcumin exists. In this study, we hypothesized that administration of tetrahydrocurcumin provides neuroprotection in a rat model of TBI.. Behavioral studies were performed by recording and analyzing beam-walking scores. The role of tetrahydrocurcumin on neurons death was assessed via Nissl staining. We then performed Western blot analyses, terminal deoxynucleotidyl transferase 2'-deoxyuridine-5'-triphosphate (dUTP) nick end labeling assays and immunofluorescence staining to evaluate autophagy and apoptosis. Phospho-protein kinase B (p-AKT) was also assessed via Western blotting.. Our data indicated that administration of tetrahydrocurcumin alleviated brain edema, attenuated TBI-induced neuron cell death, decreased the degree of apoptosis and improved neurobehavioral function, which were accompanied by enhanced autophagy and phospho-AKT after TBI. Moreover, the autophagy inhibitor 3-methyladenine and the PI3K kinase inhibitor LY294002 partially reversed the neuroprotection of tetrahydrocurcumin after TBI.. This study indicates that tetrahydrocurcumin protects neurons from TBI-induced apoptotic neuronal death, which may be through modulation autophagy and PI3K/AKT pathways. Thus, tetrahydrocurcumin may be an attractive therapeutic agent for TBI.

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Blotting, Western; Brain Injuries, Traumatic; Curcumin; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Male; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome