(+)-Borneol enantiomer ameliorates epileptic seizure via decreasing the excitability of glutamatergic transmission.

Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 µM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.

Borneol reduces sympathetic vasomotor hyperactivity and restores depressed baroreflex sensitivity in rats with renovascular hypertension.

Borneol is a bicyclic monoterpene that has long been used in traditional Chinese medicine to increase blood-brain barrier permeability and has shown promising cardiovascular effects. The present study aimed to evaluate the effect of borneol on vascular tone, blood pressure, autonomic function, and baroreflex sensitivity in normotensive and hypertensive rats. A combination of in vitro and in vivo assays was performed in 2-kidneys-1-clip hypertensive rats (2K1C) and their controls (sham). We assessed the in vivo effect of oral treatment with borneol on blood pressure, heart rate, autonomic function, and baroreflex sensitivity in sham and 2K1C rats. Additionally, the vasorelaxant effect of borneol in the superior mesenteric artery isolated from rats and its mechanism of action were evaluated. Oral administration of borneol (125 mg/kg/day) reduced blood pressure, sympathetic vasomotor hyperactivity, and serum oxidative stress and improved baroreflex sensitivity in 2K1C rats. In vessel preparations, borneol induced endothelium-independent vasodilatation after precontraction with phenylephrine or KCl (60 mM). There was no difference in the vascular effect induced by borneol in either the 2K1C or the sham group. In addition, borneol antagonized the contractions induced by CaCl2 and reversed (S)-(-)-Bay K 8644-induced contraction. These data suggest that borneol presents antihypertensive effects in 2K1C rats, which is associated with its ability to improve autonomic impairment and baroreflex dysfunction. The borneol-induced relaxation in the superior mesenteric artery involves L-type Ca2+ channel blockade. This vascular action associated with the antioxidant effect induced by borneol may be responsible, at least in part, for the in vivo effects induced by this monoterpene.

Y-2 reduces oxidative stress and inflammation and improves neurological function of collagenase-induced intracerebral hemorrhage rats.

Intracerebral hemorrhage (ICH) is a devastating disease, and there is currently no specific pharmacological treatment that can improve clinical outcomes. Y-2 sublingual tablets, each containing 30 mg edaravone and 6 mg (+)-borneol, is undergoing a phase III clinical trial for treatment of ischemic stroke in China. The purpose of the present study is to investigate the efficacy and potential mechanism of Y-2 in a rat model of collagenase IV injection induced ICH. Sublingual administration of Y-2 at the dose of 1, 3 and 6 mg/kg improved ICH-induced sensorimotor dysfunction, alleviated cell death and histopathological change, restored the hippocampal long-term potentiation (LTP), reduced brain edema and maintained blood-brain barrier (BBB) integrality in ICH rats. Further study demonstrated that Y-2 could reduce inflammatory response and oxidative stress by decreasing the levels of myeloperoxidase (MPO), ionized calcium-binding adaptor protein-1 (Iba-1), inflammatory cytokines and oxidative products, inhibit transcription factor nuclear factor-κB (NF-κB) activation, cyclooxygenase-2 (COX-2) and matrix metallopeptidase 9 (MMP-9) expression in brain tissue around in the core regions of hematoma. Importantly, the protective efficacy of Y-2 from ICH-induced injury was superior to edaravone. In conclusion, Y-2 sublingual tablets might be a promising therapeutic agent for the treatment of ICH.

Compound Danshen Dripping Pill ameliorates post ischemic myocardial inflammation through synergistically regulating MAPK, PI3K/AKT and PPAR signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Danshen Dripping Pill (CDDP), composed of Salvia miltiorrhiza Bunge, Panax notoginseng (Burkill) F.H. Chen and Borneol, is a famous traditional Chinese medicine formula which has made great achievements in the treatment of ischemic heart disease, but the profound mechanism of CDDP improving post ischemic myocardial inflammation hasn't been clearly discussed. AIM OF THE STUDY: The aim of this study was to explore the biological mechanism of constituents in CDDP synergistically improving post ischemic myocardial inflammation. MATERIALS AND METHODS: The pharmacologic studies were applied to assess the cardio protection effect of CDDP in acute myocardial ischemic rats. To identify the anti-inflammatory ingredients in CDDP, an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-luciferase reporter assay for NF-κB inhibition were used. The network pharmacology and molecular docking assay were adopted to predict targets of anti-inflammatory ingredients and then the regulation effects of these active components on their targets were also verified. RESULTS: Our results indicated that CDDP exerted an excellent cardio protection effect by reversing echocardiographic abnormalities, attenuating histopathological lesion, ameliorating circulating myocardial markers and inflammation cytokines. Tanshinol, salvianolic acid B (Sal B), tanshinone IIA (Tan IIA) and notoginsenoside R1 (NGR1) were the pivotal anti-inflammatory ingredients in CDDP. The anti-inflammatory mechanism is that tanshinol and Sal B respectively targeted on PPARγ and JNK, while Tan IIA worked on AKT1 and NGR1 bound to PI3K. CONCLUSIONS: Our results firstly demonstrated that CDDP effectively ameliorated post ischemic myocardial inflammation through simultaneously modulating MAPK, PI3K/AKT and PPAR pathways in a multi-components synergetic manner.

Borneol in cardio-cerebrovascular diseases: Pharmacological actions, mechanisms, and therapeutics.

With the coming acceleration of global population aging, the incidence rate of cardio-cerebrovascular diseases (CVDs) is increasing. It has become the leading cause of human mortality. As a natural drug, borneol (BO) not only has anti-inflammatory, anti-oxidant, anti-apoptotic, anti-coagulant activities and improves energy metabolism but can also promote drugs to enter the target organs or tissues through various physiological barriers, such as the blood-brain barrier (BBB), mucous membrane, skin. Thus, it has a significant therapeutic effect on various CVDs, which has been confirmed in a large number of studies. However, the pharmacological actions and mechanisms of BO on CVDs have not been fully investigated. Hence, this review summarizes the pharmacological actions and possible mechanisms of BO, which provides novel ideas for the treatment of CVDs.

Borneol protects against cerulein-induced oxidative stress and inflammation in acute pancreatitis mice model.

Borneol is a commonly used flavouring substance in traditional Chinese medicine, which possesses several pharmacological activities including analgesic, antiinflammatory, and antioxidant properties. The aim of this study was to investigate the effects of borneol on cerulein-induced acute pancreatitis (AP) model. Swiss albino mice were pretreated with borneol (100 and 300 mg/kg) daily for 7 days, before six consecutive injections of cerulein (50 µg/kg/hr, intraperitoneally). The protective effect of borneol was studied by biochemical, enzyme linked immunosorbent assay, histological, immunoblotting, and immunohistochemical analysis. Oral administration of borneol significantly attenuated pancreatic damage by reducing amylase, lipase levels and histological changes. Borneol attenuated cerulein-induced oxidative-nitrosative stress by decreasing malondialdehyde, nitrite levels, and elevating reduced glutathione levels. Pancreatic inflammation was ameliorated by inhibiting myeloperoxidase activity and pro-inflammatory cytokine (Interleukins and TNF-α) levels. Furthermore, borneol administration significantly increased nuclear factor E2-related factor 2 (Nrf2), superoxide dismutase (SOD1) expression and reduced phospho-NF-κB p65 expression. Treatment with borneol significantly inhibited TNF-α, IL-1ß, IL-6, and inducible nitric oxide synthase expression in cerulein-induced AP mouse model. Together, these results indicate that borneol which is currently used as US-FDA approved food adjuvant has the potential to attenuate cerulein-induced AP possibly by reducing the oxidative damage and pancreatic inflammation by modulating Nrf2/NF-κB pathway.

External application of two unrestricted herbal medicines to treat costochondritis in a young collegiate athlete: A case report.

Costochondritis (ChC), especially chronic ChC, typically manifests as spontaneous vague pain in anterior chest area and often occurs in adolescents for unknown reasons; it has prevented many collegiate athletes from participating in physical training and competitions. A 21-year-old female collegiate taekwondo athlete suffering from chronic chest pain was sent by her coaches for diagnosis and treatment. Seated motion palpation was used to identify spontaneous and motion-involved pain areas. Palpation in the supine position was used to initially rule out breast diseases. X-ray, electrocardiogram, and cardiac Doppler ultrasound were used in conjunction with myocardial enzyme testing to rule out lung and cardiovascular diseases. The patient was treated using herbal medicines applied via an external patch. The medicine was comprised of Rhizoma Corydalis and borneol, and the treatment lasted for seven weeks. For five weeks patches were applied at a frequency of two or three times per day, followed by a two-week period of once per day. The patient reported that the pain was relieved after two weeks of external herb use, and the autonomic chest pain had resolved. Re-examination after one month showed that her upper limb range of motion was close to normal, and her psychological burden had almost disappeared. It is possible to seek more active medicinal treatment and more practical external products for young athletes who is suffering chronic ChC that affects the sport training and competitive performances.

Enhanced anticancer efficiency of doxorubicin against human glioma by natural borneol through triggering ROS-mediated signal.

Doxorubicin (DOX) as a first-line chemotherapeutic drug has been widely used for therapy of human cancers. However, side effects and chemo-resistance severely blocked its clinic application. Herein, natural borneol (NB) as a novel monoterpenoid chemosensitizer was found to have the potential to increase the blood brain barrier (BBB) permeability and intracellular uptake of DOX in vitro, and synergistically enhanced DOX-induced cytotoxicity in human glioma cells. NB treatment significantly potentiated DOX-induced G2/M cell cycle arrest by triggering reactive oxygen species (ROS)-mediated DNA damage. NB also enhanced DOX-induced dysfunction of MAPKs and PI3 K/AKT pathways. Furthermore, U251 human glioma xenograft growth in vivo was also effectively inhibited by combined treatment of DOX with NB through induction of G2/M-phase arrest and antiangiogenesis. Taken together, our finding validated that NB could act as novel chemosensitizer to enhance DOX-induced anticancer efficacy, and strategy of using NB and DOX could be a high efficient way in therapy of human cancers.

Borneol alleviates brain injury in sepsis mice by blocking neuronal effect of endotoxin.

AIM: Brain injury after sepsis leads to high mortality and long-term brain dysfunction in patients. Previous studies revealed that borneol has a protective effect on the brain, but its function on sepsis associated encephalopathy (SAE) remains unknown. Herein, we investigated the protective effect of borneol against sepsis-related brain injury. MAIN METHODS: Lipopolysaccharide (LPS)-induced sepsis mice and cells were treated with borneol at the dose of 100 mg/kg by gavage or 10 µg/ml in culture, respectively. The protective effect of borneol on neurons and the microglia were assessed in vivo and in vitro. KEY FINDINGS: We observed that borneol attenuated brain neuronal and microglial inflammation in LPS-induced sepsis mice with a suppression of p-p65 and p38 signaling that were initially activated by LPS in the brain. In vitro examination confirmed that the protective effect of borneol on both neurons and microglia, and its suppressive effect on p-p65 and p38 pathways were, at least in part, direct. SIGNIFICANCE: An early protection of neurons and microglia from bacterial endotoxin during sepsis is beneficial, and borneol has the potential to protect these cells.

Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism.

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P < 0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

Progressive release of mesoporous nano-selenium delivery system for the multi-channel synergistic treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis. Controlled release, target ability, and multi-channel synergistic treatment are key factors associated with the success of AD drugs. Herein, we report a novel mesoporous nano-selenium (MSe) release delivery system (MSe-Res/Fc-ß-CD/Bor) based on the borneol (Bor) target, ß-cyclodextrin nanovalves (Fc-ß-CD) with loaded resveratrol (Res). Previous experiments have shown that MSe-Res/Fc-ß-CD/Bor first releases Bor by interacting with blood or intracellular esterases, allowing the nanosystem to pass through the blood-brain barrier (BBB). Subsequently, the Fc-ß-CD is opened by the redox (H2O2) response to the release of Res at the lesion site. We demonstrated that MSe-Res/Fc-ß-CD/Bor inhibited aggregation of ß-amyloid proteins (Aß), mitigated oxidative stress, and suppressed tau hyperphosphorylation, while protecting nerve cells and successfully improving memory impairment in APP/PS1 mice. Interestingly, compared with rivastigmine (Riv) positive drugs alone, the MSe/Fc-ß-CD/Bor loaded with Riv had a better pharmacokinetic index. These results indicate that MSe-Res/Fc-ß-CD/Bor could be a prospective drug for treating AD.

Metabolomics Study on the Effects of Salvianolic Acid B and Borneol for Treating Cerebral Ischemia in Rats by Ultra-Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry.

Salviae miltiorrliza-borneol Jun-Shi coupled-herbs have been widely used for treatment of ischemia stroke. Salvianolic acid B was the most abundant and bioactive compound of Salviae miltiorrliza and used for prevention and treatment of cerebrovascular diseases. However, the scientific intension and compatible mechanism of Salvianolic acid B - borneol combination were still unknown. A metabolomics study approach based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) combined with a pathological study has been applied to study the metabolic disturbances of cerebral ischemia and evaluate the efficacies of Sal B and Sal B/borneol against cerebral ischemia in middle cerebral artery occlusion (MCAO) rats. The neuroprotection of Sal B and Sal B/borneol was reversed through the evaluation of neurological deficits, infarct volume, and neuronal apoptosis in MCAO model. The metabonomic analysis revealed that the MCAO-induced cerebral ischemia could be ameliorated by Sal B through improving the energy metabolism, lipids metabolism, inflammatory responses, and oxidant stress. Borneol could enhance the neuroprotective effects, was associated with the increased concentration of Sal B, and attenuate the function of sphingolipid metabolism pathway in cerebral ischemia rats. These findings perhaps clarify the mechanism of neuroprotective effects of treating ischemia stroke by Sal B or Sal B/borneol preliminarily through metabolomics and push the quality promotion and the composition of borneol/Sal B in secondary development of prescription.

Neuroprotective Effects of Dibornol in Focal Cerebral Ischemia/Reperfusion in Rats.

Neuroprotective activity of 2,6-diisobornyl-4-methylphenol (Dibornol) was studied under conditions of experimental focal cerebral ischemia/reperfusion modeled by intraluminal occlusion of the left middle cerebral artery for 1 h followed by recirculation. Dibornol administered in a dose of 10 mg/kg intragastrically 24 h and 30 min before and 24 h after focal ischemia/reperfusion modeling reduced the size of the brain infarction zone by 52% (48 h after recirculation) and neurological deficit by 1.7-2.4 times in comparison with that in control animals.

The protective roles of L-borneolum, D-borneolum and synthetic borneol in cerebral ischaemia via modulation of the neurovascular unit.

OBJECTIVE: Borneol has been used to treat stroke in China since ancient times. In our previous research, we demonstrated the effect of borneol on cerebral ischaemia injury via meta-analysis. The neurovascular unit (NVU) is the structural basis of the preservation of the brain microenvironment and is believed to be a promising target in treating stroke. In this research, we explored the roles of three kinds of borneol, namely, L-borneolum (B1), D-borneolum (B2) and synthetic borneol (B3), in the NVU with permanent middle cerebral artery occluded (pMCAO) rats. METHODS: The Longa scoring method was used to evaluate nerve function deficits in the pMCAO rats. Awakening time, brain water content, brain index and brain edema rate were also measured. TTC staining was used to calculate the cerebral infarction rate. The morphology of the ischaemia penumbra brain tissue was observed via HE staining, and the neuronal denatured cell index (DCI) was calculated. An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of vascular endothelial growth factor VEGF and TNF-α in the serum. Moreover, the ultrastructures of the neurons and of the blood-brain barrier (BBB) were observed using transmission electron microscopy. The expression levels of Claudin-5, Bcl-2 and Bax in the ischaemia penumbra of pMCAO rats were detected using real-time PCR and immunohistochemistry. RESULTS: Pretreatment with B1, B2 and B3 delayed the recovery time (P < 0.01). B1 remarkably ameliorated neurological deficits 24 h after cerebral ischaemia (P < 0.05). Moreover, B1 and B3 were both able to ameliorate brain edema and the area of cerebral infarction. In addition, B1, B2 and B3 all increased serum VEGF levels and decreased serum TNF-α levels (P < 0.01). For the ultrastructure determination, the BBB and the nerve centre were significantly improved by B1, B2 and B3. The mechanistic exploration revealed that B2 and B3 protected the brain by reducing the Bax/Bcl-2 ratio (P < 0.05, P < 0.01, respectively). Immunohistochemistry suggested that B1, B2 and B3 could also enhance the expression of Claudin-5 (P < 0.01). CONCLUSION: The three kinds of borneol demonstrated different protective effects on cerebral ischaemia injury. L-Borneolum displayed the most prominent anti-cerebral ischaemia effect among them. The mechanism was most likely executed via anti-apoptosis and anti-inflammation effects and maintenance of the stability of the BBB and TJs to comprehensively improve NVU function.

Targeting S1P in Inflammatory Bowel Disease: New Avenues for Modulating Intestinal Leukocyte Migration.

Sphingosine 1 phosphate [S1P] is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors [S1PRs]. Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, the S1P/S1PR1 axis has been identified as key regulator for lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocyte migration into the mucosa in inflammatory bowel disease [IBD]. This review briefly summarises the current evidence coming from clinical studies, and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease.

(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.

Compound edaravone injection (C.EDA), a compound preparation composed of edaravone (EDA) and (+)-Borneol with the mass ratio of 4: 1, displays a better anti-inflammatory activity than EDA. However, its precise mechanism remains to be further studied. In this work, we investigated whether (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis. We found that C.EDA at 7.5 and 15mg/kg could significantly relieve the disease activity index (DAI) and reduce the loss of body weight and colon length in a dose-dependent manner, while EDA or (+)-Borneol alone only had moderate effects even at the highest dose. Additionally, ELISA revealed that C.EDA could more dramatically decrease the protein levels of inflammatory cytokines and increase the levels of anti-inflammatory cytokine than EDA or (+)-Borneol alone both in colon tissues and serum. H&E staining and IHC assay also indicated that C.EDA exhibited more prominent effects on increasing the population of M2 macrophages, decreasing M1 macrophages infiltration and protecting intestinal barrier integrity. Furthermore, in vitro studied demonstrated that C.EDA, EDA or (+)-Borneol failed in inhibiting M1 macrophages activation but could specifically induce the activation of M2 macrophages in a STAT3-dependent manner. Knockdown the expression of STAT3 successfully abolished the effect of C.EDA and EDA on promoting M2 macrophages activation. Consistent with in vivo study, C.EDA exhibited a more efficient ability of inducing M2 macrophages polarization and STAT3 activation than EDA or (+)-Borneol alone in vitro. In conclusion, we confirmed that (+)-Borneol improved the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.

Ameliorative effect of borneol, a natural bicyclic monoterpene against hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic Wistar rats.

Diabetes mellitus is a major public health problem worldwide. Oxidative stress plays a pivotal role in the pathogenesis of diabetes as it is one of the inevitable outcomes of the cellular process. The present study aims to investigate the putative antihyperglycemic, antihyperlipidemic and antioxidant efficacy of a monoterpene borneol, in comparison with glibenclamide, a standard drug for therapy of diabetes. Diabetes was induced by a single intraperitoneal injection of 40mg/kg body weight. The results of the present study showed a significant increase in the biochemical indices viz., fasting blood glucose concentration, glycated hemoglobin, urea, alanine aminotransferase, aspartate aminotransferase, malondialdehyde concentration, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and atherogenic index, with a significant decrease in body weight, plasma insulin, HOMA-ß-cell functioning index, glycogen, high-density lipoprotein cholesterol and antioxidant enzyme activities, viz., superoxide dismutase, catalase and reduced glutathione in diabetic rats when compared to controls. In addition, histology of the normal architecture of pancreas was affected in diabetic rats when compared to controls. The results for the first time reveal that oral administration of borneol for twenty eight days significantly attenuated the above mentioned alterations near to controls. Therefore, it is suggested that borneol could be a potential therapeutic antidiabetic molecule of biological relevance.

The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy.

This study aimed to investigate the synergic effects of tetramethylpyrazine phosphate (TMPP) and borneol (BO) for protecting against ischemia in the cortex and hippocampus. A rat model of global cerebral ischemia-reperfusion (GCIR) was induced by four-vessel occlusion. The results showed that TMPP (13.3 mg/kg), BO (0.16 g/kg), and their combination improved the ultrastructure of neurons, reduced the apoptosis index, and reduced the intracellular calcium content in both the cortex and hippocampus. TMPP and the combined treatment increased cortex autophagy by modulating phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) in the pAMPK-mammalian target of rapamycin (mTOR)-Unc-51-like kinase 1 (ULK1) signaling pathway, whereas BO only regulated ULK1. Moreover, BO increased neuron autophagy in the hippocampus by modulating mTOR, whereas TMPP targeted both mTOR and Beclin1. Similarly, the combination targeted both pAMPK and Beclin1. All three treatments decreased the expression of p53 and caspase-3 in the two areas. Additionally, TMPP and the combined therapy regulated Bax and Bcl-2. These results demonstrated the synergic effects between TMPP and BO for treating ischemia-reperfusion injury in the cortex and hippocampus regions. Their neuroprotective effects could be partly attributed to switching from apoptosis to protective autophagy. Additionally, the potential mechanism triggering this switching could be ascribed to the reduction of intracellular calcium content.

L-Borneol induces transient opening of the blood-brain barrier and enhances the therapeutic effect of cisplatin.

The blood-brain barrier (BBB) protects the central nervous system from external insults by limiting substance diffusion through the endothelial interface. The presence of the BBB makes drug delivery in neurological disorders very challenging. Cisplatin has been shown to be cytotoxic to glioma cells, but substantial limitations exist in its clinical applications due to difficulties in penetration across the BBB. Here, we show that L-borneol, a messenger drug widely used in traditional Chinese medicine, can induce transient disruption of the BBB after 20 min of oral administration. The permeability of the BBB began to recover within 1 h of the administration of L-borneol. Different dosages of L-borneol (100, 150, 300, 600, and 900 mg/kg) could induce significant Evans blue leakage (P<0.05). Oral administration of L-borneol elevated cisplatin concentrations in peritumoral tissue (1.24±0.12 µg/g) and tumor loci (1.41±0.13 µg/g), compared with those in the paraffin control (0.88±0.10 and 0.92±0.15 µg/g, respectively) (P<0.05). Furthermore, we found that the median survival period of tumor-bearing mice was significantly higher in the cisplatin plus L-borneol group (24.0±4.9 days) than in the cisplatin plus vehicle group (19.3±3.9 days) (P<0.05). The neurological deficits were more severe in the vehicle and cisplatin plus vehicle groups at 14 and 21 days after implantation of intracranial glioma cells than in the cisplatin plus L-borneol group. In conclusion, our results indicate that the transient opening of the BBB induced by L-borneol could enhance cisplatin accumulation within the glioma tissue and improve the survival of tumor-bearing mice.

Borneol increases blood-tumour barrier permeability by regulating the expression levels of tight junction-associated proteins.

CONTEXT: Selectively opening the blood-tumour barrier (BTB) is critical to deliver antitumour drugs from blood to tumour tissues. The BTB problem is attributed to the tight junctions (TJs), which consist of several transmembrane proteins. OBJECTIVE: To investigate whether borneol could open the BTB by affecting TJ-associated proteins ZO-1, occludin, claudin-5 and F-actin in the rat model of C6 glioma. MATERIALS AND METHODS: The plasma and brain tissue of C6 glioma rats were collected at different points after rats were administered with 35 or 140 mg/kg borneol and 0.5% CMC-Na, respectively. The permeability of BTB was assessed by cisplatin extravasation. The mRNA and protein expression levels of TJ-associated proteins were determined by QPCR, ELISA and immunohistochemistry. RESULTS: The cisplatin bioavailability in the brain tissue of C6 glioma rats administered either 35 or 140 mg/kg borneol and 0.5% CMC-Na were 415.07, 227.04 and 192.07 (mg/mL/h), respectively. The mRNA and protein expression levels of ZO-1 and F-actin began to decrease from the time point of 2 min; the lowest levels in the borneol high-dose (46.7% decrease for ZO-1 and 63.3% for F-actin compared with control) and low-dose groups (54.3% for ZO-1; 77.9% for F-actin) appeared at the time points of 30 and 45 min, respectively. Thereafter, the levels were gradually restored to the level of borneol at 0 h. Occludin and claudin-5 expression levels were not significantly modified. CONCLUSION: Borneol could selectively open the BTB and consequently increase BTB permeability, and this mechanism is associated with the down-regulation of ZO-1 and F-actin.