Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Migraine is more than the pain involved in the "migraine attack." Before the onset of pain many clinical symptoms can be observed. These symptoms may be classified as vegetative, affective, and vascular. Brain perfusion is altered during migraine attacks as well as during the intervals between attacks. These "more recent" findings are important because brain perfusion is controlled by metabolic and by neurotransmission mediated pathways: 750 ml blood/min is available in brain perfusion. The skull, on the other hand, limits the volume of blood in the brain to 130 ml. Control of the shift of blood inside the brain, with a chance of maximal blood flow or strictly limited blood volume, may be one of the most important problems in neurotransmission mediated cerebral perfusion control. The most important neurotransmission systems of cerebral perfusion control are those that are believed to be involved in affective and vegetative symptoms. It must be assumed that platelets are involved in migraine. Platelet reactivity is enhanced in migraine patients during the interval between attacks. When a migraine attack occurs a release of platelet serotonin and a further increase of platelet reactivity can be observed. Platelet activation in these cases is comparable to the situation in transient ischemic attacks. During transient ischemic attacks, platelet serotonin has been found to be enhanced in the area of transient ischemia. Serotonin is a neurotransmitter, low concentrations of which induce vasodilation, while higher concentrations induce vasoconstriction. It may be assumed that platelet serotonin is a potent vasoregulating substance that may interact in the brain vessels with the neurotransmission controlled perfusion. The hypothesis of an (inborn) instability of the interaction of cerebral neurotransmission systems in patients suffering from migraine is in accordance with the vegetative and affective symptoms in migraine, the observed imbalance of neurotransmission mediated cerebrovascular autoregulation and the irritation of platelets in migraine attacks, as well as in the interval between attacks. The "modern" treatments of migraine with acetylsalicylic acid, ergotamin and/or beta blockers are discussed in relation to this proposed hypothesis of a migraine pathophysiology.
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PMID:[Clinical aspects of pathophysiological mechanisms in migraine.]. 1841 73

Using a nonhuman primate model of surgical menopause, our laboratory has shown that ovarian hormone treatment (HT) improves 5-HT neural function in the dorsal raphe nucleus (DRN). We further hypothesize that HT may increase 5-HT neuronal resilience. Recent data from microarray analysis indicated that HT regulates gene expression in pathways that lead to apoptosis. In this study, we questioned whether HT alters protein expression in caspase-dependent and independent pathways. Ovariectomized monkeys received Silastic implants containing placebo (empty), estrogen (E) or E+ progesterone (P). A small block of the midbrain containing the DRN was dissected and subjected to subcellular fractionation, yielding cytosolic, nuclear and mitochondrial fractions (n=4/group). The pro-apoptotic protein, c-jun n-terminal kinase (JNK1) and its phosphorylation were decreased by E+P treatment in the cytosolic fraction. Downstream of JNK are proteins in the caspase-dependent and -independent pathways. First, in the caspase-dependent pathway, cytoplasmic and mitochondrial fractions were immunoblotted for Bcl-2 family members, cytochrome c, Apaf1 and XIAP. However, the expression of these proteins did not differ among treatments. Pro-caspase 3 was decreased by E+P, but there was no evidence of active caspase in any group. Then, we examined the involvement of a protein in the caspase-independent pathway, called apoptosis-inducing factor (AIF). AIF mRNA (n=3/group) and AIF mitochondrial protein tended to decrease with hormone treatment. However, AIF protein in the nuclear fraction in E+P treated monkeys was significantly reduced. This indicates that HT is reducing the translocation of AIF from mitochondria to nucleus, thus inhibiting AIF-mediated apoptosis. AIF was immunocytochemically localized to large 5-HT-like neurons of the dorsal raphe. These data suggest that in the absence of global trauma or ischemia, HT may act through the caspase-independent pathway to promote neuroprotection in the 5-HT system.
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PMID:Neuroprotective actions of ovarian hormones without insult in the raphe region of rhesus macaques. 1848 49

In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss.
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PMID:5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism. 1866 73

The involvement of 5-hydroxytryptaminergic (5-HTergic) system for the 3-nitropropionic acid (3-NPA)-induced depression of spinal reflexes was evaluated and compared with other energy deficiency condition (ischemia; glucose-free and O2-free). The monosynaptic (MSR) and polysynaptic reflex (PSR) potentials were recorded at ventral root by stimulating the corresponding dorsal root in neonatal rat spinal cord in vitro. Superfusion of 3-NPA (3.4 mM) or ischemic solution depressed the reflexes in a time-dependent manner abolishing them by 35 min. Pretreatment with pindolol (1 microM), ketanserin (10 microM) or ondansetron (0.1 microM); 5-HT1, 5-HT2, or 5-HT3 receptor antagonist, respectively, did not block the 3-NPA-induced depression of reflexes whereas, ischemia-induced depression was blocked by ondansetron. 5-HT content of the spinal cords incubated with 3-NPA (3.4 mM) for 30 min was decreased significantly (33 ng/g tissue) while increased (286 ng/g) in cords exposed to ischemic solution as compared to saline-treated cords (161 ng/g). Thus, 3-NPA-induced depression of spinal reflexes does not involve 5-HTergic pathway unlike ischemia-induced depression.
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PMID:3-Nitropropionic acid-induced depression of spinal reflexes does not involve 5-hydroxytryptaminergic system in contrast to ischemia-induced depression in neonatal rat spinal cord in vitro. 1881 48

In this study, we used in vivo brain microdialysis to examine the effects of stimulations of ischemia and/or potassium on the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens (ACC) of anesthetized rats. Ischemia (Four-vessels occlusion: 4VO) for 10 min increased DA and 5-HT release in the ACC 200-fold and 15-fold in the first experiment, respectively. In the second experiment, releases of DA and 5-HT in the ACC increased 350-400% and 150-180% by first and second K(+) stimulation, respectively, in the K(+)-K(+) groups. The 4VO treatment induced significant and massive increases of DA and 5-HT releases in the ACC, following K(+) stimulation increased 5-HT release in the Ischemia-K(+) group compared with the K(+)-K(+) group. Also the 4VO treatment in the rotenone (an inhibitor of mitochondorial electric chain)-treated rats showed lower magnitudes of DA and 5-HT massive increases compared with the non-treated control rats in 4VO groups in the third experiment. Different brain vulnerability was shown in the dopaminergic and serotonergic neurons in the same area of the ACC. These findings suggested that the ACC neurons showed a resistance to dysfunction of 10 min-ischemia and maintained neural function, monoamine synthesis and neurotransmitter releases within the transient neural damage, not chronic neural degenerations.
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PMID:Forensic studies of brain vulnerability and resistance: ischemia-induced dopamine and serotonin releases in the rat nucleus accumbens. 1934 72

The triptans, serotonin 5-HT 1B/1D agonists exemplified by sumatriptan, are an effective class of migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans have been shown to constrict human coronary artery in vitro, and there have been case reports of myocardial infarction in patients using sumatriptan. However, preclinical in vivo studies with sumatriptan in normal dogs have failed to demonstrate an effect on coronary flow. The present studies were conducted in a canine model in which regional myocardial ischemia was evoked by atrial pacing in the presence of a 40% stenosis of the left anterior descending coronary artery. Ischemic severity was quantified by changes in local epicardial electrograms (EGs) recorded in the ischemic zone. The intra-atrial administration of 10 microg x kg x min sumatriptan variably but not significantly increased the severity of regional ischemia (pre- vs. posttreatment: Delta EG: 2.00 +/- 0.17 vs. 3.05 +/- 1.15 mV). Sumatriptan at 30 microg x kg x min significantly increased ischemic severity (Delta EG: 1.88 +/- 0.19 vs. 3.32 +/- 0.58 mV, P < 0.05) concomitant with a significant reduction in coronary blood flow (8.9 +/- 0.5 vs. 7.2 +/- 0.8 mL/min, P < 0.05). These results demonstrate that a reduction in coronary flow with proischemic consequence can be modeled preclinically with sumatriptan in a canine model of cardiac stress.
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PMID:The prototype serotonin 5-HT 1B/1D agonist sumatriptan increases the severity of myocardial ischemia during atrial pacing in dogs with coronary artery stenosis. 1943 Mar 9

If normal, eupneic breathing fails, gasping is recruited. Serotonin was proposed as essential for gasping, based on findings using an in vitro mouse preparation. This preparation generates rhythmic activities of the hypoglossal nerve that are considered to be akin to both eupnea and gasping. In previous studies, gasping of in situ rat and mouse preparations continued unabated following blockers of receptors for serotonin. However, hypoglossal activity was not recorded in the mouse, and we hypothesized that its discharge during gasping might be dependent on serotonin. In the in situ mouse preparation, hypoglossal discharge had varying and inconsistent patterns during eupnea, discharging concomitant with the phrenic burst, at varying intervals between phrenic bursts, or was silent in some respiratory cycles. In eupnea, phrenic discharge was incrementing, whereas hypoglossal discharge was decrementing in 15 of 20 preparations. During ischemia-induced gasping, peak phrenic height was reached at 205 +/- 17 ms, compared with 282 +/- 27.9 ms after the start of the eupneic burst (P < 0.002). In contrast, rates of rise of hypoglossal discharge in gasping (peak at 233 +/- 25 ms) and eupnea (peak at 199 +/- 19.2 ms) were the same. The uncoupling of hypoglossal from phrenic discharge in eupnea was exacerbated by methysergide, an antagonist of serotonin receptors. These findings demonstrate that hypoglossal discharge alone cannot distinguish eupnea from gasping nor, in eupnea, can hypoglossal activity be used to differentiate neural inspiration from expiration. These findings have significant negative implications for conclusions drawn from the in vitro medullary slice of mouse.
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PMID:Discharge of the hypoglossal nerve cannot distinguish eupnea from gasping, as defined by phrenic discharge, in the in situ mouse. 1947 96

Tegaserod, a 5-HT(4) receptor agonist, has been used to treat idiopathic constipation and constipation-predominant irritable bowel disease. It has recently been suggested that tegaserod has an affinity for 5-HT(1B) receptors, which mediate vasoconstriction. As some patients have experienced cardiac ischemia during treatment with tegaserod, we assessed contractions to tegaserod in healthy and diseased human isolated coronary arteries and compared the results with those obtained using sumatriptan, an established 5-HT(1B) receptor agonist. Proximal and distal human coronary arteries were divided into sets of healthy and diseased tissues based on functional endothelial responses. Concentration-response curves to tegaserod and sumatriptan were constructed to assess their contractile potential. Tegaserod's antagonist properties at 5-HT(1B) receptors were studied by constructing concentration-response curves to sumatriptan in the absence or presence of tegaserod (1 microM). Sumatriptan induced concentration-dependent contractions, which were greater in distal than in proximal coronary artery segments. In the proximal segments, tegaserod induced contractions only at concentrations of 10 microM or higher, while in distal segments contractions were generally absent. Tegaserod did not antagonize sumatriptan-induced contractions. There was no difference between the results obtained in healthy and diseased coronary arteries. In conclusion, tegaserod induced contractions in human proximal coronary arteries at concentrations 1000 times higher than C(max) (6 mg bid). Hence, tegaserod does not exhibit a relevant vasoconstrictor potential in the human coronary artery. Further, tegaserod did not behave as an antagonist at 5-HT(1B) receptors. Additional studies may be warranted to investigate the use of 5-HT(4) agonists in patients with cardiovascular risk factors.
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PMID:Functional characterization of contractions to tegaserod in human isolated proximal and distal coronary arteries. 1961 27

Ischemia-stimulated dentate gyrus (DG) neurogenesis is hypothesized to be an etiological factor of post-stroke depression (PSD) and a potential target of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in PSD. Clinical investigations have explored the strategy of augmenting SSRIs action by combination with a 5-HT1A receptor antagonist. We investigated the relative importance of the effects on ischemia-stimulated neurogenesis and depressive-like behavior of WAY-100635 versus citalopram at different dose levels in PSD animals. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Decreased sucrose consumption was indicative of the core depressive syndrome anhedonia. Proliferating cells and their fate were monitored by bromodeoxyuridine labeling protocols up to 28 days after ischemia. Expression of the 5-HT1A receptor in DG was also examined. The current findings confirmed the ability of WAY-100635 to augment SSRIs pharmacological efficacy and SSRIs-induced elevation of post-stroke DG neurogenesis. Specifically, WAY-100635 and citalopram in different dose combinations display their relative importance in ischemia-stimulated neurogenesis probably through reinforcing serotonergic neurotransmission and/or density of 5-HT1A receptor in DG. The present data extend our understanding that increase of ischemia-induced DG neurogenesis can be interpreted as a valid index, to an extent, or even a prerequisite for an efficient co-treatment strategy.
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PMID:Involvement of serotonin neurotransmission in hippocampal neurogenesis and behavioral responses in a rat model of post-stroke depression. 2004 34

Recent observations from in vitro rodent preparations suggest an important role for the serotonin-2A (5-HT(2A)) receptor in eupneic (basal) and gasping respiratory activities, although the precise role appears to be different in different preparations. Since these in vitro preparations are typically supplied with elevated (and different) levels of K(+) to increase neuronal excitability, the role of endogenous activation of 5-HT(2A) receptors in these respiratory behaviors under "normal" levels of extracellular K(+) ([K(+)](o)) requires clarification. The current study sought to evaluate the influence of [K(+)](o) on the 5-HT(2A) receptor-mediated effects on basal respiratory activity and the phases of the hypoxic ventilatory response (HVR), including ischemia-induced gasping in an arterially-perfused adult rat preparation. Our data demonstrate that at each level of [K(+)](o) examined, blockade of 5-HT(2A) receptors increases basal phrenic burst frequency, decreases basal phrenic burst amplitude, alters basal phrenic burst pattern, and eliminates the phases of the HVR. These data support an important role for 5-HT(2A) receptors in respiratory control, and indicate the their role is not dependent on the level of [K(+)](o).
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PMID:Influence of 5-HT2A receptor blockade on phrenic nerve discharge at three levels of extracellular K+ in arterially-perfused adult rat. 2021 37


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