ABSTRACT
Bioelectronic medicine is a rapidly growing field where targeted electrical signals can act as an adjunct or alternative to drugs to treat neurological disorders and diseases via stimulating the peripheral nervous system on demand. However, current existing strategies are limited by external battery requirements, and the injury and inflammation caused by the mechanical mismatch between rigid electrodes and soft nerves. Here we report a wireless, leadless, and battery-free ferroelectret implant, termed NeuroRing, that wraps around the target peripheral nerve and demonstrates high mechanical conformability to dynamic motion nerve tissue. As-fabricated NeuroRing can act as an ultrasound receiver that converts ultrasound vibrations into electrostimulation pulses, thus stimulating the targeted peripheral nerve on demand. This capability is demonstrated by the precise modulation of the sacral splanchnic nerve to treat colitis, providing a framework for future bioelectronic medicines that offer an alternative to non-specific pharmacological approaches.
Subject(s)
Nerve Tissue , Peripheral Nerves , Peripheral Nerves/physiology , Peripheral Nervous System , Electrodes , Prostheses and ImplantsABSTRACT
BACKGROUND: Holistic biopsychosocial care has been underemphasized in perioperative pathway designs. The importance and a cost-effective way of implementing biopsychosocial care to improve postoperative pain and facilitate surgical convalescence are not well established, despite the recent popularization of Enhanced Recovery After Surgery (ERAS) programs. OBJECTIVE: We have explored the evidence and rationale of environmental enrichment (EE) as a complementary multimodal psychosocial care pathway to reduce postoperative pain, optimize patient recovery and improve existing weaknesses in surgical care. METHODS: We conducted a database search to identify and grade potential EE techniques for their evidence quality and consistency in the management of acute postoperative pain, perioperative anxiety and the etiologically comparable acute procedural or experimental pain. FINDINGS AND CONCLUSIONS: The introduction of music, virtual reality, educational information, mobile apps, or elements of nature into the healthcare environment can likely improve patients' experience of surgery. Compared with traditional psychological interventions, EE modalities are voluntary, therapist-sparing and more economically sustainable. We have also discussed practical strategies to integrate EE within the perioperative workflow. Through a combination of sensory, motor, social and cognitive modalities, EE is an easily implementable patient-centered approach to alleviate pain and anxiety in surgical patients, create a more homelike recovery environment and improve quality of life.
Subject(s)
Enhanced Recovery After Surgery , Health Facility Environment , Pain, Postoperative/prevention & control , Postoperative Care/methods , Sensory Art Therapies , HumansABSTRACT
A proportion of patients experience acute or even prolonged cognitive impairment after surgery, a condition known as postoperative cognitive dysfunction (POCD). It is characterized by impairment in different cognitive domains and neuroinflammation has been implicated as one of the inciting factors as strategies targeting inflammation tend to improve cognitive performance. Siegesbeckia Orientails L. (S. Orientails) is a common Chinese medicinal herb used for managing chronic inflammatory diseases. We investigated if pretreatment with S. Orientails before surgery confers any neuroprotective effects in postoperative animals in terms of reducing inflammation and mitigating cognitive impairment. Three-month-old male C57BL/6N mice were fed different doses of S. Orientails extract for 14 days before they underwent a laparotomy. After cognitive testing they were sacrificed on postoperative day (POD) 3. Our results showed that animals with extract pretreatment demonstrated memory improvement in a dose-dependent manner compared with control. Further, evidence for the attenuation of systemic and neuroinflammation was found in the pretreated animals, along with the inhibition of inflammatory pathways and significantly reduced tau phosphorylation in the hippocampus. Taken together, these results demonstrated a neuroprotective effect of S. Orientails in postoperative animals, indicating a therapeutic potential of S. Orientails in minimizing POCD and the possibility of utilizing this traditional Chinese medicine perioperatively.
ABSTRACT
Chronic administration of high dose opioids such as morphine is known to create intracellular oxidative stress via an opioid receptor dependent mechanism and this can interfere with cellular function. This study aimed at examining whether such changes can occur following short term exposure to high concentration of remifentanil, a potent short acting opioid. We conducted a experimental study using rat myocardium and systematically quantified tissue levels of superoxide anions, malondialdehyde (MDA) and nitrotyrosine following exposure to increasing duration (15 min, 1 or 2 h) or escalating doses of remifentanil (1 µg, 5 µg, 10 µg or 20 µg/kg/min). Concurrently the susceptibility of the heart to ischaemia reperfusion injury was assessed under the similar conditions. For any given duration of remifentanil infusion, there was increasing superoxide anions generated as the dose of remifentanil was increased. MDA concentrations were significantly increased when the animal was exposed to 10 µg/kg/min for 2h or 20 µg/kg/min for any duration. There was a trend towards an increased nitrotyrosine concentration with increasing dose of remifentanil, becoming significant when the dose was 20 µg/kg/min. The infarct limiting ability of remifentanil was compromised when the dihydroethidium fluorescence positive cell percentage exceeded 50%, MDA concentration greater than 2 nmol/mg of protein and nitrotyrosine content exceeding 1.5 µg/mg of protein. Short term high dose opioid exposure can induce oxidative changes seen previously only with chronic opioid use and this high oxidative stress environment corrupts the heart's sensitivity to be preconditioned by opioids.
Subject(s)
Ischemic Preconditioning, Myocardial/methods , Myocardial Infarction/chemically induced , Myocardium/metabolism , Oxidative Stress/drug effects , Piperidines/adverse effects , Piperidines/pharmacology , 8-Hydroxy-2'-Deoxyguanosine , Analgesics, Opioid/adverse effects , Analgesics, Opioid/pharmacology , Animals , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Dose-Response Relationship, Drug , Hemodynamics/drug effects , Male , Malondialdehyde/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Rats , Rats, Sprague-Dawley , Remifentanil , Superoxide Dismutase/metabolism , Superoxides/metabolism , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The ß isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCß is a major upstream mediator of oxidative stress in diabetes and that PKCß inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCß inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCß2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.
Subject(s)
Diabetic Cardiomyopathies/prevention & control , Hypertrophy, Left Ventricular/prevention & control , Indoles/therapeutic use , Maleimides/therapeutic use , Oxidative Stress/drug effects , Protein Kinase C/antagonists & inhibitors , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Animals , Diabetes Mellitus, Experimental/complications , Dinoprost/analogs & derivatives , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Free Radical Scavengers/pharmacology , Free Radical Scavengers/therapeutic use , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/etiology , Indoles/pharmacology , Isoprostanes/blood , Male , Maleimides/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/enzymology , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/metabolism , Protein Kinase C beta , Rats , Rats, Sprague-Dawley , Superoxides/metabolism , UltrasonographyABSTRACT
BACKGROUND: Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. CONCLUSIONS/SIGNIFICANCE: NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.
Subject(s)
Acetylcysteine/pharmacology , Adiponectin/metabolism , Allopurinol/pharmacology , Antioxidants/pharmacology , Diabetes Complications/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardium/metabolism , Acetylcysteine/therapeutic use , Adiponectin/biosynthesis , Allopurinol/therapeutic use , Animals , Antioxidants/therapeutic use , Biomarkers/metabolism , Blood Glucose/metabolism , Creatine Kinase, MB Form/blood , Diabetes Complications/drug therapy , Diabetes Complications/pathology , Diabetes Complications/physiopathology , Dinoprost/analogs & derivatives , Drug Synergism , Gene Expression Regulation/drug effects , Hemodynamics/drug effects , Interleukin-6/blood , Isoprostanes/metabolism , Male , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Adiponectin/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/bloodABSTRACT
Either isoflurane preconditioning or high-dose propofol treatment has been shown to attenuate myocardial IRI (ischaemia/reperfusion injury) in patients undergoing CABG (coronary artery bypass graft) surgery. It is unknown whether isoflurane and propofol may synergistically attenuate myocardial injury in patients. The present study investigated the efficacy of IsoPC (isoflurane preconditioning), propofol treatment (postconditioning) and their synergy in attenuating postischaemic myocardial injury in patients undergoing CABG surgery using CPB (cardiopulmonary bypass). Patients (n = 120) selected for CABG surgery were randomly assigned to one of four groups (n = 30 each). After induction, anaesthesia was maintained either with fentanyl and midazolam (control; group C); with propofol at 100 µg x kg(-1) of body weight x min(-1) before and during CPB followed by propofol at 60 µg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group P); with isoflurane 1-1.5% end tidal throughout the surgery (group I) or with isoflurane 1-1.5% end tidal before CPB and switching to propofol at 100 µg x kg(-1) of body weight x min(-1) during CPB followed by propofol at 60 µg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group IP, i.e. IsoPC plus propofol postconditioning). A joint isoflurane and propofol anaesthesia regimen synergistically reduced plasma levels of cTnI (cardiac troponin I) and CK-MB (creatine kinase MB) and f-FABP (heart-type fatty acid-binding protein) (all P < 0.05 compared with control, group P or group I) and facilitated postoperative myocardial functional recovery. During reperfusion, myocardial tissue eNOS (endothelial NO synthase) protein expression in group IP was significantly higher, whereas nitrotyrosine protein expression was lower than those in the control group. In conclusion, a joint isoflurane preconditioning and propofol anaesthesia regimen synergistically attenuated myocardial reperfusion injury in patients.
Subject(s)
Ischemic Postconditioning/methods , Ischemic Preconditioning, Myocardial/methods , Isoflurane/therapeutic use , Myocardial Reperfusion Injury/prevention & control , Propofol/therapeutic use , Aged , Anesthetics, Inhalation/therapeutic use , Anesthetics, Intravenous/therapeutic use , Antioxidants/metabolism , Coronary Artery Bypass/adverse effects , Cytokines/metabolism , Drug Synergism , Female , Hemodynamics , Humans , Inflammation Mediators/metabolism , Male , Middle Aged , Nitric Oxide Synthase Type III/metabolism , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
UNLABELLED: The expression of NF-κB in the spinal cord is associated with neuropathic pain. However, little is known about its expression beyond the spinal cord. Here we examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions. After chronic constriction injury (CCI) of the sciatic nerve, NF-κB (p65) expression was significantly increased in the ipsilateral spinal cord. In contrast, the NF-κB expression in the contralateral primary somatosensory cortex was decreased with no significant differences seen in the thalamus. In the contralateral anterior cingulate cortex, the NF-κB expression was increased significantly on day 14 as compared with the sham group. In the contralateral amygdala, the NF-κB expression showed a time-dependent downregulation after CCI, which became significant on day 14. MK-801 reduced nociceptive behaviors and reversed the direction of NF-κB expression. These results indicate that the CCI-induced expression of p65 NF-κB is both time-dependent and region-specific, in areas that process both sensory-discriminative and motivational-affective dimensions of pain. PERSPECTIVE: This article presents a spatiotemporal mapping of the NF-κB expression in spinal and supraspinal regions after peripheral nerve injury. These findings point to an involvement of NF-κB beyond the spinal cord in both the sensory discriminative and emotional affective aspects of neuropathic pain processing.
Subject(s)
Gene Expression Regulation/physiology , NF-kappa B/metabolism , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/pathology , Somatosensory Cortex/metabolism , Spinal Cord/metabolism , Animals , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Dizocilpine Maleate/therapeutic use , Functional Laterality/physiology , Gene Expression Regulation/drug effects , Male , Neuralgia/drug therapy , Neuralgia/etiology , Neuralgia/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Pain Measurement , Peripheral Nervous System Diseases/complications , Rats , Synaptotagmin I/metabolism , Thalamus/metabolism , Thalamus/pathologyABSTRACT
Supplementation of L-arginine, a nitric oxide precursor, during the late phase of myocardial ischemia/reperfusion increases myocyte apoptosis and exacerbates myocardial injury, but the underlying mechanism is unclear. During myocardial ischemia/reperfusion, apoptosis of endothelial cells precedes that of cardiomyocyte. Tumor necrosis factor-alpha (TNF) production is increased during myocardial ischemia/reperfusion, which may exacerbate myocardial injury by inducing endothelial cell apoptosis. We postulated that L-arginine may exacerbate TNF-induced endothelial cell apoptosis by enhancing peroxynitrite-mediated nitrative stress. Cultured human umbilical vein endothelial cells were either not treated (control) or treated with TNF alone or with TNF in the presence of L-arginine, the nonselective nitric oxide synthase inhibitor N (omega)-nitro-L-arginine (L-NNA), propofol (an anesthetic that scavenges peroxynitrite), or L-arginine plus propofol, respectively, for 24 hours. TNF increased intracellular superoxide and hydrogen peroxide production accompanied by increases of inducible nitric oxide synthase (iNOS) protein expression and nitric oxide production. This was accompanied by increased protein expression of nitrotyrosine, a fingerprint of peroxynitrite and an index of nitrative stress, and increased endothelial cell apoptosis. L-arginine did not enhance TNF-induced increases of superoxide and peroxynitrite production but further increased TNF-induced increase of nitrotyrosine production and exacerbated TNF-mediated cell apoptosis. L-NNA and propofol, respectively, reduced TNF-induced nitrative stress and attenuated TNF cellular toxicity. The L-arginine-mediated enhancement of nitrative stress and TNF toxicity was attenuated by propofol. Thus, under pathological conditions associated with increased TNF production, L-arginine supplementation may further exacerbate TNF cellular toxicity by enhancing nitrative stress.