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A review of sternal closure techniques

Alhalawani AM, Towler MR

J Biomater Appl, 2013 Nov;28(4):483-97.
PMID: 23812580 DOI: 10.1177/0885328213495426

Sternotomy and sternal closure occur prior to and post cardiac surgery, respectively. Although post-operative complications associated with poor sternal fixation can result in morbidity, mortality, and considerable resource utilization, sternotomy is preferred over other methods such as lateral thoracotomy. Rigid sternal fixation is associated with stability and reduced incidence of post-operative complications. This is a comprehensive review of the literature evaluating in vivo, in vitro, and clinical responses to applying commercial and experimental surgical tools for sternal fixation after median sternotomy. Wiring, interlocking, plate-screw, and cementation techniques have been examined for closure, but none have experienced widespread adoption. Although all techniques have their advantages, serious post-operative complications were associated with the use of wiring and/or plating techniques in high-risk patients. A fraction of studies have analyzed the use of sternal interlocking systems and only a single study analyzed the effect of using kryptonite cement with wires. Plating and interlocking techniques are superior to wiring in terms of stability and reduced rate of post-operative complications; however, further clinical studies and long-term follow-up are required. The ideal sternal closure should ensure stability, reduced rate of post-operative complications, and a short hospitalization period, alongside cost-effectiveness.
Fulltext Raman spectroscopy applied to the noninvasive detection of monosodium urate crystal deposits

Curran DJ, Rubin L, Towler MR

Clin Med Insights Arthritis Musculoskelet Disord, 2015;8:55-8.
PMID: 26327784 DOI: 10.4137/CMAMD.S29061

An off-the-shelf Raman Spectrometer (RS) was used to noninvasively determine the presence of monosodium urate (MSU) crystals on the metatarsophalangeal joint (MTPJ) of a single gout sufferer. The spectrum sourced from the clinically diagnosed gout sufferer was compared to that sourced from an age-matched healthy subject scanned using the same protocol. Minimal signal processing was conducted on both spectra. Peaks characteristic of MSU crystals were evident on the spectrum sourced from the gout sufferer and not on the spectrum from the healthy control.

Study done in Canada
Inorganic hemostats: The state-of-the-art and recent advances

Pourshahrestani S, Zeimaran E, Djordjevic I, Kadri NA, Towler MR

Mater Sci Eng C Mater Biol Appl, 2016 Jan 1;58:1255-68.
PMID: 26478429 DOI: 10.1016/j.msec.2015.09.008

Hemorrhage is the most common cause of death both in hospitals and on the battlefield. The need for an effective hemostatic agent remains, since all injuries are not amenable to tourniquet use. There are many topical hemostatic agents and dressings available to control severe bleeding. This article reviews the most commonly used inorganic hemostats, subcategorized as zeolite and clay-based hemostats. Their hemostatic functions as well as their structural properties that are believed to induce hemostasis are discussed. The most important findings from in vitro and in vivo experiments are also covered.
The impact of gallium content on degradation, bioactivity, and antibacterial potency of zinc borate bioactive glass

Rahimnejad Yazdi A, Torkan L, Stone W, Towler MR

J Biomed Mater Res B Appl Biomater, 2018 Jan;106(1):367-376.
PMID: 28152268 DOI: 10.1002/jbm.b.33856

Zinc borate glasses with increasing gallium content (0, 2.5, 5, 10, and 15 Wt % Ga) were synthesized and their degradation, bioactivity in simulated body fluid (SBF), and antibacterial properties were investigated. ICP measurements showed that increased gallium content in the glass resulted in increased gallium ion release and decreased release of other ions. Degradability declined with the addition of gallium, indicating the formation of more symmetric BO3 units with three bridging oxygens and asymmetric BO3 units with two bridging oxygens in the glass network as the gallium content in the series increased. The formation of amorphous CaP on the glass surface after 24 h of incubation in SBF was confirmed by SEM, XRD, and FTIR analyses. Finally, antibacterial evaluation of the glasses using the agar disc-diffusion method demonstrated that the addition of gallium increased the antibacterial potency of the glasses against P. aeruginosa (Gram-negative) while decreasing it against S. epidermidis (Gram-positive); considering the ion release trends, this indicates that the gallium ion is responsible for the glasses' antibacterial behavior against P. aeruginosa while the zinc ion controls the antibacterial activity against S. epidermidis. The statistical significance of the observed trends in the measurements were confirmed by applying the Kruskal-Wallis H Test. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 367-376, 2018.
Well-ordered mesoporous silica and bioactive glasses: promise for improved hemostasis

Pourshahrestani S, Kadri NA, Zeimaran E, Towler MR

Biomater Sci, 2018 Dec 18;7(1):31-50.
PMID: 30374499 DOI: 10.1039/c8bm01041b

Immediate control of uncontrolled bleeding and infection are essential for saving lives in both combat and civilian arenas. Inorganic well-ordered mesoporous silica and bioactive glasses have recently shown great promise for accelerating hemostasis and infection control. However, to date, there has been no comprehensive report assessing their specific mechanism of action in accelerating the hemostasis process and exerting an antibacterial effect. After providing a brief overview of the hemostasis process, this review presents a critical overview of the recently developed inorganic mesoporous silica and bioactive glass-based materials proposed for hemostatic clinical applications and specifically investigates their unique characteristics that render them applicable for hemostatic applications and preventing infections. This article also identifies promising new research directions that should be undertaken to ascertain the effectiveness of these materials for hemostatic applications.
Antibacterial properties of poly (octanediol citrate)/gallium-containing bioglass composite scaffolds

Zeimaran E, Pourshahrestani S, Djordjevic I, Pingguan-Murphy B, Kadri NA, Wren AW, et al.

J Mater Sci Mater Med, 2016 Jan;27(1):18.
PMID: 26676864 DOI: 10.1007/s10856-015-5620-2

Bioactive glasses may function as antimicrobial delivery systems through the incorporation and subsequent release of therapeutic ions. The aim of this study was to evaluate the antimicrobial properties of a series of composite scaffolds composed of poly(octanediol citrate) with increased loads of a bioactive glass that releases zinc (Zn(2+)) and gallium (Ga(3+)) ions in a controlled manner. The antibacterial activity of these scaffolds was investigated against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. The ability of the scaffolds to release ions and the subsequent ingress of these ions into hard tissue was evaluated using a bovine bone model. Scaffolds containing bioactive glass exhibited antibacterial activity and this increased in vitro with higher bioactive glass loads; viable cells decreased to about 20 % for the composite scaffold containing 30 % bioactive glass. The Ga(3+) release rate increased as a function of time and Zn(2+) was shown to incorporate into the surrounding bone.
Fulltext Congestive heart failure: experimental model

Corno AF, Cai X, Jones CB, Mondani G, Boyett MR, Jarvis JC, et al.

Front Pediatr, 2013;1:33.
PMID: 24400279 DOI: 10.3389/fped.2013.00033

Surgically induced, combined volume and pressure overload has been used in rabbits to create a simplified and reproducible model of acute left ventricular (LV) failure.
Fulltext A Novel Glass Polyalkenoate Cement for Fixation and Stabilisation of the Ribcage, Post Sternotomy Surgery: An ex-Vivo Study

Alhalawani AM, Curran DJ, Pingguan-Murphy B, Boyd D, Towler MR

J Funct Biomater, 2013;4(4):329-57.
PMID: 24956193 DOI: 10.3390/jfb4040329

This study investigates the use of gallium (Ga) based glass polyalkenoate cements (GPCs) as a possible alternative adhesive in sternal fixation, post sternotomy surgery. The glass series consists of a Control (CaO-ZnO-SiO2), and LGa-1 and LGa-2 which contain Ga at the expense of zinc (Zn) in 0.08 mol% increments. The additions of Ga resulted in increased working time (75 s to 137 s) and setting time (113 to 254 s). Fourier Transform Infrared (FTIR) analysis indicated that this was a direct result of increased unreacted poly(acrylic acid) (PAA) and the reduction of crosslink formation during cement maturation. LGa samples (0.16 wt % Ga) resulted in an altered ion release profile, particularly for 30 days analysis, with maximum Ca2+, Zn2+, Si4+ and Ga3+ ions released into the distilled water. The additions of Ga resulted in increased roughness and decreased contact angles during cement maturation. The presence of Ga has a positive effect on the compressive strength of the samples with strengths increasing over 10 MPa at 7 days analysis compared to the 1 day results. The additions of Ga had relatively no effect on the flexural strength. Tensile testing of bovine sterna proved that the LGa samples (0.16 wt % Ga) are comparable to the Control samples.
Bioactive glass reinforced elastomer composites for skeletal regeneration: A review

Zeimaran E, Pourshahrestani S, Djordjevic I, Pingguan-Murphy B, Kadri NA, Towler MR

Mater Sci Eng C Mater Biol Appl, 2015 Aug;53:175-88.
PMID: 26042705 DOI: 10.1016/j.msec.2015.04.035

Biodegradable elastomers have clinical applicability due to their biocompatibility, tunable degradation and elasticity. The addition of bioactive glasses to these elastomers can impart mechanical properties sufficient for hard tissue replacement. Hence, a composite with a biodegradable polymer matrix and a bioglass filler can offer a method of augmenting existing tissue. This article reviews the applications of such composites for skeletal augmentation.
Investigating the addition of SiO₂-CaO-ZnO-Na₂O-TiO₂ bioactive glass to hydroxyapatite: Characterization, mechanical properties and bioactivity

Yatongchai C, Placek LM, Curran DJ, Towler MR, Wren AW

J Biomater Appl, 2015 Nov;30(5):495-511.
PMID: 26116020 DOI: 10.1177/0885328215592866

Hydroxyapatite (Ca10(PO4)6(OH)2) is widely investigated as an implantable material for hard tissue restoration due to its osteoconductive properties. However, hydroxyapatite in bulk form is limited as its mechanical properties are insufficient for load-bearing orthopedic applications. Attempts have been made to improve the mechanical properties of hydroxyapatite, by incorporating ceramic fillers, but the resultant composite materials require high sintering temperatures to facilitate densification, leading to the decomposition of hydroxyapatite into tricalcium phosphate, tetra-calcium phosphate and CaO phases. One method of improving the properties of hydroxyapatite is to incorporate bioactive glass particles as a second phase. These typically have lower softening points which could possibly facilitate sintering at lower temperatures. In this work, a bioactive glass (SiO2-CaO-ZnO-Na2O-TiO2) is incorporated (10, 20 and 30 wt%) into hydroxyapatite as a reinforcing phase. X-ray diffraction confirmed that no additional phases (other than hydroxyapatite) were formed at a sintering temperature of 560 ℃ with up to 30 wt% glass addition. The addition of the glass phase increased the % crystallinity and the relative density of the composites. The biaxial flexural strength increased to 36 MPa with glass addition, and there was no significant change in hardness as a function of maturation. The pH of the incubation media increased to pH 10 or 11 through glass addition, and ion release profiles determined that Si, Na and P were released from the composites. Calcium phosphate precipitation was encouraged in simulated body fluid with the incorporation of the bioactive glass phase, and cell culture testing in MC-3T3 osteoblasts determined that the composite materials did not significantly reduce cell viability.
Silver Nanoparticle Coated Bioactive Glasses--Composites with Dex/CMC Hydrogels: Characterization, Solubility, and In Vitro Biological Studies

Wren AW, Hassanzadeh P, Placek LM, Keenan TJ, Coughlan A, Boutelle LR, et al.

Macromol Biosci, 2015 Aug;15(8):1146-58.
PMID: 25923463 DOI: 10.1002/mabi.201500109

Silver (Ag) coated bioactive glass particles (Ag-BG) were formulated and compared to uncoated controls (BG) in relation to glass characterization, solubility and microbiology. X-ray diffraction (XRD) confirmed a crystalline AgNP surface coating while ion release studies determined low Ag release (<2 mg/L). Cell culture studies presented increased cell viability (127 and 102%) with lower liquid extract (50 and 100 ml/ml) concentrations. Antibacterial testing of Ag-BG in E. coli, S. epidermidis and S. aureus significantly reduced bacterial cell viability by 60-90%. Composites of Ag-BG/CMC-Dex Hydrogels were formulated and characterized. Agar diffusion testing was conducted where Ag-BG/hydrogel composites produced the largest inhibition zones of 7 mm (E. coli), 5 mm (S. aureus) and 4 mm (S. epidermidis).
Fulltext In vivo detection of monosodium urate crystal deposits by Raman spectroscopy-a pilot study

Abhishek A, Curran DJ, Bilwani F, Jones AC, Towler MR, Doherty M

Rheumatology (Oxford), 2016 Feb;55(2):379-80.
PMID: 26342227 DOI: 10.1093/rheumatology/kev339

Study done in England
Fulltext In-House Packed Porous Graphitic Carbon Columns for Liquid Chromatography-Mass Spectrometry Analysis of N-Glycans

Young C, Condina MR, Briggs MT, Moh ESX, Kaur G, Oehler MK, et al.

Front Chem, 2021;9:653959.
PMID: 34178940 DOI: 10.3389/fchem.2021.653959

Protein glycosylation is a common post-translational modification that modulates biological processes such as the immune response and protein trafficking. Altered glycosylation profiles are associated with cancer and inflammatory diseases, as well as impacting the efficacy of therapeutic monoclonal antibodies. Consisting of oligosaccharides attached to asparagine residues, enzymatically released N-linked glycans are analytically challenging due to the diversity of isomeric structures that exist. A commonly used technique for quantitative N-glycan analysis is liquid chromatography-mass spectrometry (LC-MS), which performs glycan separation and characterization. Although many reversed and normal stationary phases have been utilized for the separation of N-glycans, porous graphitic carbon (PGC) chromatography has become desirable because of its higher resolving capability, but is difficult to implement in a robust and reproducible manner. Herein, we demonstrate the analytical properties of a 15 cm fused silica capillary (75 µm i.d., 360 µm o.d.) packed in-house with Hypercarb PGC (3 µm) coupled to an Agilent 6550 Q-TOF mass spectrometer for N-glycan analysis in positive ion mode. In repeatability and intermediate precision measurements conducted on released N-glycans from a glycoprotein standard mixture, the majority of N-glycans reported low coefficients of variation with respect to retention times (≤4.2%) and peak areas (≤14.4%). N-glycans released from complex samples were also examined by PGC LC-MS. A total of 120 N-glycan structural and compositional isomers were obtained from formalin-fixed paraffin-embedded ovarian cancer tissue sections. Finally, a comparison between early- and late-stage formalin-fixed paraffin-embedded ovarian cancer tissues revealed qualitative changes in the α2,3- and α2,6-sialic acid linkage of a fucosylated bi-antennary complex N-glycan. Although the α2,3-linkage was predominant in late-stage ovarian cancer, the alternate α2,6-linkage was more prevalent in early-stage ovarian cancer. This study establishes the utility of in-house packed PGC columns for the robust and reproducible LC-MS analysis of N-glycans.
Gallium-containing mesoporous bioactive glass with potent hemostatic activity and antibacterial efficacy

Pourshahrestani S, Zeimaran E, Adib Kadri N, Gargiulo N, Samuel S, Naveen SV, et al.

J Mater Chem B, 2016 Jan 07;4(1):71-86.
PMID: 32262810 DOI: 10.1039/c5tb02062j

Haemorrhage remains the leading cause of potentially survivable death in both military and civilian populations. Although a large variety of hemostatic agents have been developed, many of them have an inadequate capacity to induce hemostasis and are not effective in killing bacteria. In recent years, mesoporous bioactive glasses (MBGs) were found to be effective in inducing hemostasis. However, the materials may not be considered as ideal hemostats since they do not offer antimicrobial activity. The gallium ion (Ga+3) not only exhibits antibacterial properties but also accelerates the blood coagulation cascade. The aim of this study was to develop MBGs containing various concentrations of Ga2O3 (1, 2 & 3 mol%) via the evaporation-induced self-assembly (EISA) process and investigate whether the addition of Ga3+ would induce both hemostatic and antibacterial effects. The results indicated that the incorporation of lower Ga2O3 content (1 mol%) into the MBG system improved structural properties including the specific surface area, mesopore size and pore volume as well as the release of silicon and calcium ions. The bioactive glass was found to stimulate blood coagulation, platelet adhesion and thrombus generation and exerted an antibacterial effect against both Escherichia coli and Staphylococcus aureus. Likewise, Ga-doped MBGs showed excellent cytocompatibility even after 3 days, with the 1% Ga2O3-containing MBG attaining the best biocompatibility that render them safe hemostatic agents for stopping bleeding. This study demonstrated that the lowest Ga2O3-substituted MBG can be a potent candidate for controlling haemorrhage and wound infection.
Titanium addition influences antibacterial activity of bioactive glass coatings on metallic implants

Rodriguez O, Stone W, Schemitsch EH, Zalzal P, Waldman S, Papini M, et al.

Heliyon, 2017 Oct;3(10):e00420.
PMID: 29034340 DOI: 10.1016/j.heliyon.2017.e00420

In an attempt to combat the possibility of bacterial infection and insufficient bone growth around metallic, surgical implants, bioactive glasses may be employed as coatings. In this work, silica-based and borate-based glass series were synthesized for this purpose and subsequently characterized in terms of antibacterial behavior, solubility and cytotoxicity. Borate-based glasses were found to exhibit significantly superior antibacterial properties and increased solubility compared to their silica-based counterparts, with BRT0 and BRT3 (borate-based glasses with 0 and 15 mol% of titanium dioxide incorporated, respectively) outperforming the remainder of the glasses, both borate and silicate based, in these respects. Atomic Absorption Spectroscopy confirmed the release of zinc ions (Zn(2+)), which has been linked to the antibacterial abilities of glasses SRT0, BRT0 and BRT3, with inhibition effectively achieved at concentrations lower than 0.7 ppm. In vitro cytotoxicity studies using MC3T3-E1 osteoblasts confirmed that cell proliferation was affected by all glasses in this study, with decreased proliferation attributed to a faster release of sodium ions over calcium ions in both glass series, factor known to slow cell proliferation in vitro.
Fulltext Antimicrobial stewardship and targeted therapies in the changing landscape of maternal sepsis

Shah NM, Charani E, Ming D, Cheah FC, Johnson MR

J Intensive Med, 2024 Jan;4(1):46-61.
PMID: 38263965 DOI: 10.1016/j.jointm.2023.07.006

Pregnant and postnatal women are a high-risk population particularly prone to rapid progression to sepsis with significant morbidity and mortality worldwide. Moreover, severe maternal infections can have a serious detrimental impact on neonates with almost 1 million neonatal deaths annually attributed to maternal infection or sepsis. In this review we discuss the susceptibility of pregnant women and their specific physiological and immunological adaptations that contribute to their vulnerability to sepsis, the implications for the neonate, as well as the issues with antimicrobial stewardship and the challenges this poses when attempting to reach a balance between clinical care and urgent treatment. Finally, we review advancements in the development of pregnancy-specific diagnostic and therapeutic approaches and how these can be used to optimize the care of pregnant women and neonates.
Fulltext Association of psychological factors, patients' knowledge, and management among patients with erectile dysfunction

Huri HZ, Mat Sanusi ND, Razack AH, Mark R

Patient Prefer Adherence, 2016;10:807-23.
PMID: 27257374 DOI: 10.2147/PPA.S99544

BACKGROUND: Erectile dysfunction (ED) is one of the most common health problems in men. ED can significantly affect a man's psychological well-being and overall health.
PURPOSE: To investigate the association of psychological factors, patients' knowledge, and management among ED patients.
PATIENTS AND METHODS: A total of 93 patients with an age range from 31 to 81 years who have undergone treatment for ED were included in this study.
RESULTS: It was found that the feeling of blame (P=0.001), guilt (P=0.001), anger or bitterness (P=0.001), depression (P=0.001), feeling like a failure (P=0.001), and the feeling of letting down a partner during intercourse (P=0.001) were significantly associated with ED. Age was also found to be significantly associated with patients' psychological scale (P=0.004). In addition, the majority of patients in this study practice the right method of administration of ED therapy. However, no significant correlation was found between patients' knowledge of ED therapy and demographic characteristics.
CONCLUSION: This study concluded that ED does affect psychological well-being of people. In addition, patient's knowledge about ED and its management is also crucial in ensuring that the patient achieves optimal therapeutic outcomes from ED therapy.
MALDI Mass Spectrometry Imaging of Early- and Late-Stage Serous Ovarian Cancer Tissue Reveals Stage-Specific N-Glycans

Briggs MT, Condina MR, Ho YY, Everest-Dass AV, Mittal P, Kaur G, et al.

Proteomics, 2019 11;19(21-22):e1800482.
PMID: 31364262 DOI: 10.1002/pmic.201800482

Epithelial ovarian cancer is one of the most fatal gynecological malignancies in adult women. As studies on protein N-glycosylation have extensively reported aberrant patterns in the ovarian cancer tumor microenvironment, obtaining spatial information will uncover tumor-specific N-glycan alterations in ovarian cancer development and progression. matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is employed to investigate N-glycan distribution on formalin-fixed paraffin-embedded ovarian cancer tissue sections from early- and late-stage patients. Tumor-specific N-glycans are identified and structurally characterized by porous graphitized carbon-liquid chromatography-electrospray ionization-tandem mass spectrometry (PGC-LC-ESI-MS/MS), and then assigned to high-resolution images obtained from MALDI-MSI. Spatial distribution of 14 N-glycans is obtained by MALDI-MSI and 42 N-glycans (including structural and compositional isomers) identified and structurally characterized by LC-MS. The spatial distribution of oligomannose, complex neutral, bisecting, and sialylated N-glycan families are localized to the tumor regions of late-stage ovarian cancer patients relative to early-stage patients. Potential N-glycan diagnostic markers that emerge include the oligomannose structure, (Hex)6 + (Man)3 (GlcNAc)2 , and the complex neutral structure, (Hex)2 (HexNAc)2 (Deoxyhexose)1 + (Man)3 (GlcNAc)2 . The distribution of these markers is evaluated using a tissue microarray of early- and late-stage patients.
Translating N-Glycan Analytical Applications into Clinical Strategies for Ovarian Cancer

Briggs MT, Condina MR, Klingler-Hoffmann M, Arentz G, Everest-Dass AV, Kaur G, et al.

Proteomics Clin Appl, 2019 05;13(3):e1800099.
PMID: 30367710 DOI: 10.1002/prca.201800099

Protein glycosylation, particularly N-linked glycosylation, is a complex posttranslational modification (PTM), which plays an important role in protein folding and conformation, regulating protein stability and activity, cell-cell interaction, and cell signaling pathways. This review focuses on analytical techniques, primarily MS-based techniques, to qualitatively and quantitatively assess N-glycosylation while successfully characterizing compositional, structural, and linkage features with high specificity and sensitivity. The analytical techniques explored in this review include LC-ESI-MS/MS and MALDI time-of-flight MS (MALDI-TOF-MS), which have been used to analyze clinical samples, such as serum, plasma, ascites, and tissue. Targeting the aberrant N-glycosylation patterns observed in MALDI-MS imaging (MSI) offers a platform to visualize N-glycans in tissue-specific regions. The studies on the intra-patient (i.e., a comparison of tissue-specific regions from the same patient) and inter-patient (i.e., a comparison of tissue-specific regions between different patients) variation of early- and late-stage ovarian cancer (OC) patients identify specific N-glycan differences that improve understanding of the tumor microenvironment and potentially improve therapeutic strategies for the clinic.
Fulltext Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

Chia JSM, Izham NAM, Farouk AAO, Sulaiman MR, Mustafa S, Hutchinson MR, et al.

Front Pharmacol, 2020;11:92.
PMID: 32194397 DOI: 10.3389/fphar.2020.00092

Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone's anti-neuropathic effects. The present study was conducted to determine zerumbone's modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists- prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration.

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