Neuroprotective Effect Of Baicalein Research Articles

Neuroprotective Effect of Baicalein Against Oxaliplatin-Induced Peripheral Neuropathy: Impact on Oxidative Stress, Neuro-inflammation and WNT/β-Catenin Signaling.

Oxaliplatin, an effective anti-cancer agent used in the treatment of colorectal cancer, isassociated with severe dose-limiting side effects like peripheral neuropathy, which currently remains a major unmet clinical need. This study was designed to investigate the possible neuroprotective potential of a bioflavonoid, baicalein in an experimental model of oxaliplatin-induced peripheral neuropathy. Rats were administered with a dose of 4mg/kg oxaliplatin i.p. twice per week for four weeks, and were evaluated for behavioral and functional nerve parameters, followed by biochemical, immunohistochemical and western blot analysis. This study shows that baicalein reversed oxaliplatin-induced behavioral deficits and significantly prevented oxaliplatin-induced sensory nerve conduction deficits in rats. Molecular analysis revealed baicalein significantly strengthened the antioxidant defense system by enhancing the expression of MnSOD, HO-1, and GSH levels. Baicalein treatment neutralized the oxaliplatin-induced neuroinflammation, which was evident from the significant loss of inflammatory mediators like TNF-α, IL-6 and a shunted NF-κB nuclear translocation. Additionally, baicalein treatment resulted in a significant downregulation of active β-catenin, Wnt5b and Wnt3a proteins. In line with the in vivo evidences, baicaleintreatment in Neuro2a cells attenuated oxaliplatin-induced ROS, mitochondrial superoxide levels and improved neuritogenesis.Additionally, baicalein did not alter the cell viability of oxaliplatin in HCT-116 cell line. Collectively, these results suggest that baicalein may be useful for management of peripheral neuropathy associated with oxaliplatin.

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis.

Posttraumatic epilepsy (PTE) is a prevalent type of acquired epilepsy secondary to traumatic brain injury, and is characterized by repeated seizures. Traditional antiepileptic drugs have minimal response in preventing posttraumatic epileptic seizures. It is essential for the development of new therapeutic strategy. Our previous work disclosed a potent neuroprotective role of baicalein, a flavonoid extracted from Scutellaria baicalensis Georgi, against inherited epilepsy in rats. Whether baicalein has protective potential in posttraumatic epileptic seizures and the possible molecular mechanism remain elusive. Additionally, the brain is vulnerable to lipid peroxidation-induced damage due to high consumption of oxygen and abundant polyunsaturated fatty acids in neuronal membranes. Our present investigation aimed to elucidate whether baicalein exerts neuroprotective effects on posttraumatic epileptic seizures by inhibiting ferroptosis, a newly discovered lipid peroxidation-dependent cell death modality. We found that baicalein significantly reduced seizure score, number of seizures, and average seizure duration in an iron chloride (FeCl3)-induced PTE mouse model. The neuroprotective effect of baicalein was also validated in a ferric ammonium citrate (FAC)-induced HT22 hippocampal neuron damage model. Moreover, in vitro, baicalein could remarkably decrease ferroptotic indices (lipid reactive oxygen species, 4-hydroxynonenal, and prostaglandin endoperoxide synthase 2) and inhibit the expression of 12/15-lipoxygenase (12/15-LOX) in an iron-induced HT22 cell damage model. These findings were also validated in a mouse PTE model. It was concluded that baicalein exerted neuroprotective effects against posttraumatic epileptic seizures via suppressing ferroptosis and 12/15-LOX was likely to be involved in baicalein’s neuroprotection.

Neuroprotective Effects of Baicalein on Acrolein-induced Neurotoxicity in the Nigrostriatal Dopaminergic System of Rat Brain.

Elevated levels of acrolein, an α,β-unsaturated aldehyde are detected in the brain of patients with Parkinson's disease (PD). In the present study, the neuroprotective effect of baicalein (a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi) on acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using local infusion of acrolein in the substantia nigra (SN) of rat brain. Systemic administration of baicalein (30mg/kg, i.p.) significantly attenuated acrolein-induced elevations in 4-hydroxy-2-noneal (a product of lipid peroxidation), N-(3-formyl-3,4-dehydropiperidino)lysine (a biomarker of acrolein-conjugated proteins), and heme-oxygenase-1 levels (a redox-regulated protein) in the infused SN, indicating that baicalein inhibited acrolein-induced oxidative stress and protein conjugation. Furthermore, baicalein reduced acrolein-induced elevations in glial fibrillary acidic protein (a biomarker of activated astrocytes), ED-1 (a biomarker of activated microglia), and mature cathepsin B levels (a cysteine lysosomal protease), suggesting that baicalein attenuated acrolein-induced neuroinflammation. Moreover, baicalein attenuated acrolein-induced caspase 1 activation (a pro-inflammatory caspase) and interleukin-1β levels, indicating that baicalein prevented acrolein-induced inflammasome activation. In addition, baicalein significantly attenuated acrolein-induced caspase 3 activation (a biomarker of apoptosis) as well as acrolein-induced elevation in receptor interacting protein kinase (RIPK) 3 levels (an initiator of necroptosis), indicating that baicalein attenuated apoptosis and necroptosis. At the same time, baicalein mitigated acrolein-induced reduction in dopamine levels in the striatum ipsilateral to acrolein-infused SN. In conclusion, our data suggest that baicalein is neuroprotective via inhibiting oxidative stress, protein conjugation, and inflammation. Furthermore, baicalein prevents acrolein-induced program cell deaths, suggesting that baicalein is therapeutically useful for slowing PD progression.

Baicalein ameliorates cognitive deficits in epilepsy-like tremor rat

Baicalein has been shown to possess various pharmacological actions. The current work was designed to assess the neuroprotection of baicalein against cognitive deficits in epilepsy-like tremor rat (TRM). Epileptic characteristics and memory functions were assessed by electroencephalograms recording and Morris water maze test, respectively. The changes of oxidative indicators including malondialdehyde (MDA), catalase (CAT), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, glutathione (GSH), glutathione peroxidase (GSH-PX) and 8-isoprostane were measured using corresponding commercial kits. Real-time RT-PCR and immunoassay were employed to detect activities of various inflammatory mediators such as NF-κB p65, TNF-α, IL-1β, IL-6 and IL-10. Western blot analysis was performed to determine heat shock protein (HSP) 70 and mitogen-activated protein kinases (MAPKs) (including ERK, JNK and p38) proteins. Our results illustrated that baicalein significantly ameliorated epileptiform activity and cognitive deficits in TRM. Besides, reduced oxidative stress and inflammatory responses were also found in TRM treated with baicalein. Furthermore, there were evident alterations of HSP70 and MAPK cascades at protein levels after 14-day pretreatment with baicalein. It was concluded that the neuroprotective effect of baicalein against cognitive dysfunction might be associated with suppressing oxidative stress, inhibiting inflammation and mediating HSP70 as well as MAPK cascades in absence-like TRM.

Cell Type-Specific Dependency on the PI3K/Akt Signaling Pathway for the Endogenous Epo and VEGF Induction by Baicalein in Neurons versus Astrocytes

The neuroprotective effect of baicalein is generally attributed to inhibition of 12/15-lipoxygenase (12/15-LOX) and suppression of oxidative stress, but recent studies showed that baicalein also activates hypoxia-inducible factor-α (HIF1α) through inhibition of prolyl hydrolase 2 (PHD2) and activation of the phosphatidylinositide-3 kinase (PI3K)/Akt signaling pathway. Yet, the significance and regulation of prosurvival cytokines erythropoietin (Epo) and vascular endothelial growth factor (VEGF), two transcriptional targets of HIF1α, in baicalein-mediated neuroprotection in neurons and astrocytes remains unknown. Here we investigated the causal relationship between the PI3K/Akt signaling pathway and Epo/VEGF expression in baicalein-mediated neuroprotection in primary rat cortical neurons and astrocytes. Our results show that baicalein induced Epo and VEGF expression in a HIF1α- and PI3K/Akt-dependent manner in neurons. Baicalein also protected neurons against excitotoxicity in a PI3K- and Epo/VEGF-dependent manner without affecting neuronal excitability. In contrast, at least a 10-fold higher concentration of baicalein was needed to induce Epo/VEGF production and PI3K/Akt activity in astrocytes for protection of neurons. Moreover, only baicalein-induced astrocytic VEGF, but not Epo expression requires HIF1α, while PI3K/Akt signaling had little role in baicalein-induced astrocytic Epo/VEGF expression. These results suggest distinct mechanisms of baicalein-mediated Epo/VEGF production in neurons and astrocytes for neuroprotection, and provide new insights into the mechanisms and potential of baicalein in treating brain injury in vivo.

Neuroprotective effect of baicalein in patients with Parkinson's disease

Baicalein, a flavonoid compound extracted from dried roots of traditional Chinese medicine Scutellaria baicalensis, has been widely applied as an antioxidant and anti-inflammatory agent. With continuous studies on its mechanisms, recent findings suggest that baicalein has some effect on neuroprotection and improvement of clinical symptoms in neurodegenerative diseases such as Parkinson's disease. Recent studies showed that its neuroprotective efficacy is closely related to such functions as antiinflammatory, antioxidative stress, protecting chondriosome, inhibiting glutamate neurotoxicity, promoting nerve growth and inhibiting alpha-synuclein protein-aggregate activities. The aim of this article is to summarize the neuroprotective effects of baicalein in Parkinson's disease.

Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity

Objectives: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses anti-oxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH.a cells.Methods and results: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH.a cells.Discussion: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage.

Baicalein protects the brain against neuron impairments induced by MPTP in C57BL/6 mice

Many studies of Parkinson's disease suggest that oxidative stress is involved in the neurodegenerative process. Baicalein has been shown to have antioxidant effects. The present study examines the effect of baicalein on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in C57BL/6 mice. MPTP treatment impaired spontaneous motor activity and rotarod performance, but baicalein improved this deficit. Moreover, baicalein at 280 and 560mg/kg exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the substantia nigra, demonstrated by the immunohistological, morphological and behavioral outcomes. MPTP treatment also decreased dopamine levels in the striatum. However, treatment with baicalein attenuated these decreases in dopamine levels by changing dopamine catabolism and inhibiting dopamine turnover. The neuroprotective effect of baicalein on dopaminergic neurons may partly be due to its antioxidant properties. Therefore, we speculate that baicalein might be a promising candidate for prevention or treatment of oxidative stress-related neurodegenerative disorders such as Parkinson's disease.

Neuroprotective Effect of Baicalein on Hydrogen Peroxide-Mediated Oxidative Stress and Mitochondrial Dysfunction in PC12 Cells

Oxidative stress plays an important role in many neurodegenerative disorders. In this study, the effect of baicalein, a natural flavonoid isolated from the root of Scutellaria baicalensis G., on hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells were investigated. Exposure of PC12 cells to 0.15 mM H2O2 for 20 min induced a significant decrease in cell viability accompanied by increased oxidative stress, mitochondrial dysfunction, downregulation of Bcl-2, upregulation of Bax, and cell apoptosis. Pretreatment of PC12 cells with baicalein inhibited H2O2-induced cell viability loss, intracellular reactive oxygen species generation, and lipid peroxidation in a dose-dependent manner. Meanwhile, baicalein potentially inhibited H2O2-induced cell apoptosis characterized with the DNA fragment. And the mitochondrial pathway involving the mitochondrial dysfunction associated with cell apoptosis including membrane potential loss, the release of cytochrome c, the downregulation of Bcl-2, upregulation of Bax induced by H2O2 were also abrogated in the presence of baicalein. Taken together, these results suggest that baicalein can block H2O2-induced apoptosis by prevention of oxidative stress as well as regulation of Bcl-2 family members and suppression of mitochondria dysfunction, which might be beneficial for the treatment of oxidative stress in aging and age-associated neurodegenerative diseases.

Post‐injury baicalein improves histological and functional outcomes and reduces inflammatory cytokines after experimental traumatic brain injury

Traumatic brain injury (TBI) triggers a complex series of inflammatory responses that contribute to secondary tissue damage. The aim of this study was to investigate the effect of baicalein, a flavonoid possessing potent anti-inflammatory properties, on functional and histological outcomes and inflammatory cytokine expression, following TBI in rats. Rats subjected to controlled cortical impact injury were injected with baicalein (30 mg kg(-1)) or vehicle immediately after injury or daily for 4 days. Neurological status was evaluated using the rotarod, adhesive removal, modified neurological severity scores and beam walk tests. Contusion volume and neuronal degeneration were measured using cresyl violet and FluoroJade B (FJB) histochemistry. Levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) mRNA and protein were assessed by real-time quantitative reverse transcriptase-PCR, enzyme-linked immunosorbent assay and immunohistochemistry. Single-dose and multiple-dose treatment with baicalein significantly improved functional recovery and reduced contusion volumes up to day 28 post-injury, although multiple-dose baicalein was the more effective treatment. Single-dose baicalein also significantly reduced the number of degenerating neurons (31%) on post-injury day 1 as indicated by FJB staining. These changes were associated with significantly decreased levels, at the contusion site, of TNF-alpha, IL-1 beta and IL-6 mRNA at 6 h, and cytokine protein on day 1 post-injury. Post-injury treatment with baicalein improved functional and histological outcomes and reduced induction of proinflammatory cytokines in rat TBI. The neuroprotective effect of baicalein may be related to a decreased inflammatory response following the injury.

Neuroprotective effect of baicalein against MPTP neurotoxicity: Behavioral, biochemical and immunohistochemical profile

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes the damage of dopaminergic neurons as seen in Parkinson's disease (PD). Oxidative stress has been implicated in the pathogenesis of PD. Baicalein, isolated from the traditional Chinese herbal medicine Huangqin (Scutellaria baicalensis Georgi), has been shown to have antioxidant effects. Here we investigated the effect of baicalein on MPTP-induced neurotoxicity in mice. Pretreatment with baicalein for a week was followed by challenge with MPTP for 4 consecutive days; the subsequent behavioral, biochemical and immunohistochemical manifestations in mice were determined and compared to those in untreated mice and mice challenged only with MPTP. The present study showed that baicalein could improve the abnormal behavior in MPTP-treated mice. The protective effect may be caused by increasing the levels of DA and 5-HT in the striatum, increasing the counts of dopaminergic neurons, inhibiting oxidative stress and the astroglia response. These results suggest that baicalein possesses potent neuroprotective activity and may be a potential anti-Parkinson's disease drug that is worthy of further study.