Ischemic stroke and mitochondria: mechanisms and targets

Protoplasma - Stroke is one of the main causes of mortality and disability in most countries of the world. The only way of managing patients with ischemic stroke is the use of intravenous tissue...     

The immunology of stroke: from mechanisms to translation

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.     

Hypergravity and opioid-mediated pain suppression in rats

It is known that pain suppression in animals is induced by certain environmental stimulus. However, little is known about the effects of gravitational alteration on the nociceptive responses in rats. A recent study indicated that Fos protein expression was strongly induced in the vestibular-related brainstem regions of rats that were exposed to 2 G hypergravity (Gustave Dit Duflo et al., 2000). A number of studies indicate that Fos expression is induced in the brain by various kinds of stress. We showed that either long-term exposure or short-term exposure to 2 G hypergravity elevated the nociceptive threshold in the rat skin surfaces, in concomitant with Fos induction in the hypothalamus including the arcuate nucleus and paraventricular nucleus (Kumei et al., 2000). We have examined the possible involvement of beta-endorphin, an endogenous opioid, in the hypergravity-induced analgesic effects on rats and its counteraction by naloxone, an opioid receptor antagonist.     

Heat shock response and ageing: mechanisms and applications

Ageing is associated with a decrease in the ability of cells to cope with environmental challenges. This is due partly to the attenuation of a primordial stress response, the so-called heat shock (HS) response, which induces the expression of heat shock proteins (HSPs), composed of chaperones and proteases. The attenuation of the HS response during ageing may be responsible for the accumulation of damaged proteins as well as abnormal regulation of cell death. Maintenance of the HS response by repeated mild heat stress causes anti-ageing hormetic effects on cells and organisms. Here, we describe the molecular mechanism and the state of the HS response as well as the role of specific HSPs during ageing, and discuss the possibility of hormetic modulation of ageing and longevity by repeated mild stress.     

Ionizing radiation induces opioid-mediated analgesia in male mice

The effects of exposure to ionizing radiation on the nociceptive thresholds of CF-1 mice were examined. Significant increases in thermal response latencies, indicative of analgesia were observed after exposure to either high or low doses of radiation. However, the onset of analgesia occurred significantly more rapidly after treatment with the high doses. Administration of the opiate antagonist, naloxone, blocked and reversed the analgesic effects of both the high and low dose of radiation. These findings support the hypothesis that exposure to ionizing radiation results in opioid-mediated analgesia.     

Intraventricular insulin decreases kappa opioid-mediated sucrose intake in rats

The hormone insulin acts in the central nervous system (CNS) as a regulator of body adiposity and food intake. Recent work from our laboratory has provided evidence that one way by which insulin may decrease food intake is by decreasing the rewarding properties of food. Evidence from others suggests that endogenous opioids may mediate the palatable properties of foods, and insulin may decrease nonfood-related reward via interaction with some CNS kappa opioid systems. In the present study we examined the ability of insulin to interact with exogenous or endogenous kappa opioids to modulate feeding of palatable sucrose pellets by nondeprived rats. Insulin (5 mU intracerebroventricular (i.c.v.), t=−3 h) completely reversed the ability of the exogenous kappa agonist U50,488 (26 μg, i.c.v., t=−15 min) to stimulate 90-min sucrose feeding (211±32% reduced to 125±23% of 90-min baseline intake). Further, i.c.v. insulin (5 mU, t=−3 h) interacted with a subthreshold dose of the kappa receptor antagonist norbinaltorphimine (5 μg, i.c.v., t=−15 min) to decrease the 90-min sucrose intake baseline (77±11% versus 109±10% of 90 min baseline intake, insulin/norbinaltorphimine versus norbinaltorphimine). Together these studies provide new evidence that insulin in the CNS may decrease the action of CNS kappa opioid system(s) that mediate palatable feeding.     

Heat transport mechanisms in vascular tissues: a model comparison

We have conducted a parametric comparison of three different vascular models for describing heat transport in tissue. Analytical and numerical methods were used to predict the gross temperature distribution throughout the tissue and the small-scale temperature gradients associated with thermally significant blood vessels. The models are: an array of unidirectional vessels, an array of countercurrent vessels, and a set of large vessels feeding small vessels which then drain into large vessels. We show that three continuum formulations of bioheat transfer (directed perfusion, effective conductivity, and a temperature-dependent heat sink) are limiting cases of the vascular models with respect to the thermal equilibration length of the vessels. When this length is comparable to the width of the heated region of tissue, the local temperature changes near the vessels can be comparable to the gross temperature elevation. These results are important to the use of thermal techniques used to measure the blood perfusion rate and in the treatment of cancer with local hyperthermia.     

Nocistatin and nociceptin given centrally induce opioid-mediated gastric mucosal protection

Nociceptin (N/OFQ) and nocistatin (NST) are two endogenous neuropeptides derived from the same precursor protein, preproN/OFQ. The aim of the present work was to study the effect of NST on the ethanol-induced mucosal damage compared with that of N/OFQ following intracerebroventricular (i.c.v.) administration in the rat and to analyze the mechanism of the gastroprotective action. It was found that both NST and N/OFQ reduced the mucosal lesions in the same dose range (0.2–1 nmol i.c.v.), but in higher doses (2–5 nmol i.c.v.) the gastroprotective effect of both peptides was highly diminished. The gastroprotective effect of N/OFQ (1 nmol), but not that of NST (1 nmol), was reduced by the selective nociceptin receptor antagonist J-113397 (69 nmol i.c.v.). Similarly, decrease of the gastroprotective effect was observed after the combination of NST (1 nmol) with N/OFQ (0.6 or 1 nmol). However, addition of the gastroprotective effects was observed, when lower dose (0.2 nmol) of NST was given prior to N/OFQ (0.6 nmol). The gastroprotective effect of both N/OFQ and NST was antagonized by naloxone (27 nmol), β-funaltrexamine (20 nmol), naltrindole (5 nmol) and norbinaltorphimine (14 nmol), the μ-, δ- and κ-opioid receptor antagonists, respectively, given i.c.v. The mucosal protection was significantly decreased after bilateral cervical vagotomy. The present findings suggest that NST similar to N/OFQ, may also induce gastric mucosal protective action initiated centrally in a vagal-dependent mechanism. Opioid component is likely to be involved in the gastroprotective effect of both NST and N/OFQ.     

Heat shock proteins and DNA repair mechanisms: an updated overview

Heat shock proteins (HSPs), also known as molecular chaperones, participate in important cellular processes, such as protein aggregation, disaggregation, folding, and unfolding. HSPs have cytoprotective functions that are commonly explained by their antiapoptotic role. Their involvement in anticancer drug resistance has been the focus of intense research efforts, and the relationship between HSP induction and DNA repair mechanisms has been in the spotlight during the past decades. Because DNA is permanently subject to damage, many DNA repair pathways are involved in the recognition and removal of a diverse array of DNA lesions. Hence, DNA repair mechanisms are key to maintain genome stability. In addition, the interactome network of HSPs with DNA repair proteins has become an exciting research field and so their use as emerging targets for cancer therapy. This article provides a historical overview of the participation of HSPs in DNA repair mechanisms as part of their molecular chaperone capabilities.     

Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies

Cerebral damage as a consequence of glutamate-mediated excitotoxicity represents a major consequence of stroke. However, the development of effective clinical treatments for this potentially devastating condition has been largely unsuccessful to date, despite promising basic research. This review will focus on the latest advances in our understanding of the excitotoxic process including the release of glutamate as a neurotransmitter and the potential contribution of complexins, the important role of astrocytes, including its involvement in glutamate uptake, alterations in glutamate transporter levels, reversed glutamate uptake, and the vesicular release of glutamate. Recent progress in our understanding of the involvement of excitotoxicity in white matter injury following ischemic insults is also discussed, as is oxidative stress and ischemic tolerance, along with an update on the use of treatment strategies with potential therapeutic benefit including stimulation of neurogenesis. Such key issues are at the heart of future interventions directed at limiting the extent of the excitotoxic process, and remain a viable consideration for effective stroke management.     

Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials

Mitochondrial damage is a critical contributor to stroke‐induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.     

Heat acclimation: phenotypic plasticity and cues to the underlying molecular mechanisms

Acclimation, in contrast to evolutionary adaptation, is a “within life time phenotypic adaptation” resulting in a widening of the dynamic regulatory range of body temperature. Increased efficiency and capacity of the thermoregulatory effectors, and delayed onset of the temperature threshold for thermal injury, contribute to the beneficial effects of acclimation. Reprogrammed gene expression and changes in cellular signaling underlie these responses. Constitutive elevation of the inducible heat shock protein (HSP) 72 kDa provides cytoprotection and delays thermal injury without the need for de novo HSP synthesis upon thermal stress. The time window for evocation of heat acclimation is the early phase of acclimation, the short-term heat acclimation (STHA), with accelerated sympathetic excitability and a drop in plasma thyroxin playing an essential role. An important consequence of thermal acclimation is the development of cross-tolerance between heat acclimation and ischemia/reperfusion insults. The beneficial implications of this feature are discussed.     

Anti-inflammatory and opioid-mediated effects of melatonin on experimental peritonitis in chickens

The immunomodulatory properties of melatonin (Mel) are generally recognized but the mechanisms of its action are not fully understood. In mammals, some of the immunomodulatory effects of Mel are mediated by opioids synthesized by immune cells under its influence. The present study was performed to examine whether Mel-induced opioids are involved in the immunomodulatory activity of Mel in chickens. Experimental peritonitis was evoked by a single ip injection of thioglycollate (TG), and half of the birds were pre-treated with Mel. Some of the Mel-treated birds were additionally pre-treated with naltrexone, an antagonist of opioid receptors. Control birds received an injection of saline, Mel or were untreated. At specific post-injection intervals chickens were sacrificed, the peritoneal cavity was flushed out and peritoneal leukocytes (PTLs) were counted. The activity of PTLs was measured in vitro by the level of reactive oxygen species (ROS). Splenocytes were isolated aseptically and mitogen-stimulated in vitro proliferation was assessed. In PTLs and splenocytes the expression of opioid (proopiomelanocortin and proenkephalin) genes was also examined. Mel exerted a bi-phasic effect on TG-induced peritonitis in chickens: initially it blocked the development of peritonitis, decreasing the number of PTLs and intracellular ROS level (anti-inflammatory action), and thereafter an increase in both PTL number and ROS level was observed (pro-inflammatory action). The pro-inflammatory effect occurred a few hours after the induction of expression of the proenkephalin gene in PTLs and both the proenkephalin and proopiomelanocortin genes in splenocytes. These effects were prevented by naltrexone, suggesting involvement of the opiatergic mechanism.     

Heat stress differentially impacts key calcification mechanisms in reef-building corals

Coral Reefs - Coral reefs are increasingly threatened by climate change, mass bleaching events and ocean acidification (OA). Coral calcification, a process that is critical to build and maintain...     

Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a mu-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by coadministration with a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester, during phases 1 and 2 in the formalin test. Spinal coadministration of a mu-opioid receptor agonist, morphine, with a subeffective dose of BLF produced a much more highly potentiated analgesia than that produced by morphine alone during phases 1 and 2 in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a mu-opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2, or by NG-nitro-l-arginine methyl ester. In the tail-flick test, continuous spinal infusion of morphine via an osmotic minipump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via an NO-mediated mechanism.