Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA1 cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA1 neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p less than 0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA1 degeneration to only 20.7% (p less than 0.0001 vs. vehicle-treated group). However, treatment with the non-kappa analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA1 neurons. Our results are consistent with the hypothesis that kappa-receptor stimulation is associated with improved postischemic neuronal preservation.
Stroke 1988 Aug
PMID:Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils. 284 Jul 59

Like other opioids, the dynorphins play a role in wide variety of physiological parameters, including pain regulation, motor activity, cardiovascular regulation, respiration, temperature regulation, feeding behavior, hormone balance, and the response to shock or stress. The dynorphins are unusual if not unique, however, in that they frequently modulate the activity of other opioids, rather than having direct effects themselves. Thus, they are not analgesic in brain, yet they antagonize opioid analgesia in naive animals and potentiate it in tolerant animals. They have little or no effect by themselves on temperature regulation or respiration, but they enhance the acute effects of morphine on these parameters. Their beneficial effects on stroke are like those of opioid antagonists rather than like agonists. Consistent with such a wide variety of physiological effects, the dynorphins bind to all three of the major opioid receptor types in brain, mu, delta, and kappa, though they exhibit some preference toward kappa sites. They also seem to interact with other physiologically relevant sites; though on the basis of their sensitivity to des-Tyr fragments of dynorphine and/or their insensitivity to naloxone, these sites have been termed "non-opioid". No second messenger systems have been directly associated with dynorphine binding, but several likely candidates exist.
 ...
PMID:Pharmacology of dynorphin. 289 33

We studied the effect of dynorphin A-(1-13), dynorphin A-(1-17), des-tyr dynorphin A-(2-17) (inactive at opioid receptor) or normal saline (NS) microinjected into the paraventricular nucleus (PVN) (n = 9/treatment) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and left ventricular stroke work (LVSW) during fixed-volume hemorrhage in conscious rats. Microinjection of dynorphin A-(1-13) (6 nmol) into PVN at 15 min following the termination of fixed volume hemorrhage (8 ml/300 g) significantly decreased MAP from 50 min to 2 hr postinjection (P < 0.05 compared to animals receiving NS), while dynorphin A-(1-17) (6 nmol) significantly decreased MAP from 30 min up to 2 hr postinjection (P < 0.05). Microinjection of des-tyr dynorphin A-(2-17) (6 nmol) into the PVN did not significantly affect MAP following hemorrhage. Recovery of MAP in the dynorphin A-(1-13) and dynorphin A-(1-17) groups following hemorrhage was found to be significantly attenuated compared to the NS group (P < 0.05 and P < 0.01, respectively). Dynorphin A-(1-13) increased heart rate at 20 min and decreased stroke volume at 60 min after microinjection directly into the PVN following hemorrhage when compared with the NS group (P < 0.05). Both dynorphin A-(1-13) and dynorphin A-(1-17) significantly decreased LVSW after PVN injection following hemorrhage compared to NS group (both P < 0.05). No significant effects were observed on CO following microinjection of active or inactive opioid peptides into the PVN following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of dynorphin microinjection in the paraventricular nucleus on the hemodynamic response to hemorrhage in the rat. 791 78

The region surrounding the anteroventral part of the third ventricle (AV3V) is important for the regulation of cardiovascular homeostasis. In the present study we investigated the effect of the kappa-opioid receptor agonists dynorphin A-(1-17) and dynorphin A-(1-13) microinjected into the AV3V region on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and left ventricular stroke work (LVSW) during fixed-volume hemorrhage in conscious rats. During fixed-volume hemorrhage (8 ml/300 g), dynorphin A-(1-17) (6 nmol), microinjected into the AV3V, significantly decreased MAP up to 30 min postinjection (P < 0.05). Recovery of MAP, SV, and LVSW in the dynorphin A-(1-17) group following hemorrhage was found to be significantly attenuated compared to that in animals receiving microinjection of normal saline (NS) vehicle into the AV3V (P < 0.05). Hypothalamic microinjection of dynorphin A-(1-13) (6 nmol) also attenuated the recovery of SV following hemorrhage compared with the NS group (P < 0.05). No significant effects were observed on HR or CO following microinjection of dynorphin into the AV3V region. The results of this study suggest that activation of the kappa-opiate receptor system in the AV3V region of the hypothalamus can attenuate the compensatory cardiovascular responses to hemorrhage.
 ...
PMID:Effect of dynorphin microinjection in the anterior hypothalamus (AV3V) region on the hemodynamic response to hemorrhage in the rat. 809 73

Central nervous system (CNS) inflammation in cases such as head trauma, infection and stroke has been associated with the occurrence of epileptic seizures. Microglia, the principal immune cells in the brain, readily become activated in response to injury, infection or inflammation. The bacterial endotoxin lipopolysaccharide (LPS) induces the activation of microglia and the production of proinflammatory factors including nitric oxide (NO) and prostaglandins (PGs). We examined the effect of LPS on seizure susceptibility of mice, by using the sensitive test, threshold of clonic seizures induced by i.v. infusion of pentylenetetrazole. LPS decreased the seizure threshold in a dose- and time-dependent manner. Pretreatment of mice with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester or cyclooxygenase inhibitor, piroxicam or the opioid receptor antagonist, (-)-naloxone completely reversed the proconvulsant effect of LPS. These results indicate that NO, PGs and endogenous opioid peptides seem to be involved in LPS-induced decrease in seizure threshold.
 ...
PMID:The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice: involvement of proinflammatory factors: nitric oxide and prostaglandins. 1464 73

Central neuropathic pain (CNP) is pain resulting from damage to the central nervous system. Up till now, it has not been possible to identify a common lesion or pharmacological deficit in these patients. This preliminary study in a group of patients with CNP with predominantly post-stroke pain, demonstrates that there is significantly less opioid receptor binding in a number of cortical and sub-cortical structures that are mostly, but not exclusively, within the medial pain system in patients compared to age-matched pain-free controls. The reductions in opioid receptor binding within the medial system were observed mainly in the dorsolateral (Brodman area 10) and anterior cingulate (Brodman area 24 with some extension into area 23) and insula cortices and the thalamus. There were also reductions in the lateral pain system within the inferior parietal cortex (Brodman area 40). These changes in binding could not be accounted for by the cerebral lesions shown by CT or MRI, which were outside the areas of reduced binding and the human pain system. To our knowledge this is the first systematic demonstration of a reduction in opioid receptor-binding capacity in neurones within the human nociceptive system in patients with CNP. This may be a key common factor resulting in undamped nociceptor activity within some of the structures that are predominantly within the medial nociceptive system. If confirmed, these findings may explain why certain patients with CNP require high doses of synthetic opiates to achieve optimum analgesia. The findings also raise the possibility of new pharmacological approaches to treatment.
 ...
PMID:Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET. 1532 79

Perioperative management of geriatric patients is becoming an important component in anaesthetic practice in the 21st century. This phenomenon is due to the fact that people aged 65 and over are the segment with the fastest growing population. Thus, it is estimated that by the year 2025 20 % of the population in the western hemisphere will be > 65 years of age. Currently, elderly patients comprise one-third of all operations, and one out of two patients older than 65 years of age will undergo an operation in their lifetime. The dramatic change in demographics of surgical patients will have a tremendous impact on the use of anaesthetics. Older patients facing surgery can generally be expected to be a more complex case than their younger counterparts. They have more systemic diseases (e. g. cardiac, pulmonary, endocrine), and usually these diseases have advanced to more serious stages. These patients may suffer disability, both physical and mental, and may show differences in the pharmacokinetic as well as the pharmacodynamic of compounds such as opioids. While neuronal numbers, dendrites and synapses decline with age and the ventricular volume triples, cerebral circulation is similar to young adults, although there is a reduction in cerebral blood flow (CBF). This is because of the lower unit weight, lower CBF and CMRO (2), which are tightly coupled in aging where autoregulation is preserved. However, because of a decline in dopaminergic, serotonergic, cholinergic and GABAergic transmitters, anticholinergic compounds (atropine, scopolamine) as well as some anaesthetics such as ketamine, benzodiazepines or even propofol may produce delirium and/or an increase in efficacy when given together with opioids. Therefore it is mandatory to consider a pharmacologic interaction with a potentiation and/or an addition in effects of other drugs when judging the net action of opioids in the elderly. Physicians and nurses treating geriatric patients tend to have an unfounded level of fear of complications associated with treating perioperative pain. Although it is known that inadequate analgesia may delay recovery, the treatment of perioperative pain in the geriatric patient remains inadequate, even relative to younger patients. It is well established that there is increased responsiveness to the effects of opioids in the elderly. This may result in an increased risk of respiratory depression, while especially the elderly female patient demonstrates an increase in the duration of effects, but the risk of nausea is not augmented. Increased sensitivity of older patients to systemic opioids mostly involves pharmacokinetic factors such as a higher proportion of unbound and active substances as well as changes in drug redistribution. Because of a 40 % reduction in stroke volume in the elderly, there is a protracted redistribution of opioids to the liver. This results in a prolonged metabolisation, a lesser inactivation over time followed by an increase in duration of effects, mainly impairment of respiration. To a much lesser extent, pharmacodynamic factors with an increased response at opioid receptor sites have to be considered. Although the mechanisms causing differences of opioid action in the elderly may be complex, the clinical implications are not. They include slow titration of opioids to allow for long circulation times, lower total doses because of increased sensitivity, and anticipation of a longer duration of action because of reduced clearance. Since elderly patients present multimorbidity, therapy of chronic pain has to be considered in the light of multidrug intake, which, due to interaction, results in marked side-effects, and a prolonged duration of action. Those opioids should be used which, due to their pharmacokinetic properties, have a reduced volume of distribution, present a low plasma protein binding and finally result in the formation of no pharmacologically active metabolites.
 ...
PMID:[Use of opioids in the elderly -- pharmacokinetic and pharmacodynamic considerations]. 1533 29

The early phase of preconditioning (PC) lasts 2 to 3 hours and protects against myocardial infarction, but not against stunning. In contrast, the late phase of PC lasts for 3 to 4 days and protects against both myocardial stunning and infarction, making this phenomenon more clinically relevant. Late PC is a genetic reprogramming of the heart that involves the activation of several stress-responsive genes, which ultimately results in the development of a cardioprotective phenotype. Sublethal ischemic insults release chemical signals (nitric oxide [NO], adenosine, and reactive oxygen species) that trigger a series of signaling events (eg, activation of protein kinase C, Src protein tyrosine kinases, Janus kinases 1/2, and nuclear factor-kappaB) and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, heme oxygenase-1, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. In addition to ischemia, heat stress, exercise, and cytokines can also induce a similar series of events. Perhaps most importantly, many pharmacologic agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists) can mimic the effects of ischemia in inducing the late phase of PC, suggesting that this phenomenon might be exploited therapeutically. The purpose of this review is to summarize the mechanisms that underlie the late phase of ischemic PC.
Stroke 2004 Nov
PMID:Delayed adaptation of the heart to stress: late preconditioning. 1545 41

Microdialysis is currently optimized to sample the extrasynaptic pool. As such, the technique has facilitated discovery of ischemia-induced excitotoxic glutamate overflow (Benveniste H, Drejer J, Schousboe A, Diemer NH, 1987, Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J. Neurochem., 49, 729-734) and adenosinergic sleep drive (Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW, 1997, Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science, 276 (5316), 1265-1268); and is proving essential for clinical monitoring of glutamate and cellular metabolites in stroke and head trauma (Sarrafzadeh AS, Sakowitz OW, Kiening KL, Benndorf G, Lanksch WR, Unterberg AW. Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients? Crit. Care Med. 2002, 30 (5): 1062-1070). Study of the origin of extrasynaptic glutamate sampled with microdialysis has advanced understanding of extrasynaptic signal processing (Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 2002, 22 (20): 9134-9141; Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW, 2003, Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat. Neurosci., 6, 743-749) in the CNS. Microdialysis studies furthermore demonstrate that synaptic pools of some neurotransmitters spill into the extrasynaptic space. For this reason, microdialysis has provided a window into the synaptic pool that has significantly advanced understanding of neurotransmitter control of behavior (Tanda G, Pontieri FE, Di Chiara G, 1997, Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science, 276, 2048-2050). Nonetheless, ability to sample synaptic pools of neurotransmitters is limited. Here we summarize evidence that microdialysis often fails to sample synaptic pools of neurotransmitters, such as glutamate and GABA because of rapid clearance and limited diffusion of these neurotransmitters from the synapse. Moreover, we consider means to move the dialysis membrane closer to the synapse to facilitate sampling of the synaptic pool of these neurotransmitters by minimizing tissue trauma, decreasing probe size and increasing temporal resolution.
 ...
PMID:Sampling glutamate and GABA with microdialysis: suggestions on how to get the dialysis membrane closer to the synapse. 1558 42

The detrimental effect of severe hypoxia (SH) on neurons can be mitigated by hypoxic preconditioning (HPC), but the molecular mechanisms involved remain unclear, and an understanding of these may provide novel solutions for hypoxic/ischemic disorders (e.g. stroke). Here, we show that the delta-opioid receptor (DOR), an oxygen-sensitive membrane protein, mediates the HPC protection through specific signaling pathways. Although SH caused a decrease in DOR expression and neuronal injury, HPC induced an increase in DOR mRNA and protein levels and reversed the reduction in levels of the endogenous DOR peptide, leucine enkephalin, normally seen during SH, thus protecting the neurons from SH insult. The HPC-induced protection could be blocked by DOR antagonists. The DOR-mediated HPC protection depended on an increase in ERK and Bcl 2 activity, which counteracted the SH-induced increase in p38 MAPK activities and cytochrome c release. The cross-talk between ERK and p38 MAPKs displays a "yinyang" antagonism under the control of the DOR-G protein-protein kinase C pathway. Our findings demonstrate a novel mechanism of HPC neuroprotection (i.e. the intracellular up-regulation of DOR-regulated survival signals).
 ...
PMID:Oxygen-sensitive {delta}-opioid receptor-regulated survival and death signals: novel insights into neuronal preconditioning and protection. 1568 1


1 2 3 4 Next >>