Direct admission vs. secondary transfer for mechanical thrombectomy: long-term clinical outcomes from a single Polish Comprehensive Stroke Centre.

INTRODUCTION: We aimed to compare 3-month clinical outcomes after mechanical thrombectomy (MT) in patients transferred directly to a comprehensive stroke centre ('mothership', MS) to the outcomes of patients transferred secondarily from primary stroke centres ('drip-and-ship', DAS) in Lubelskie province, the third largest province in Poland. MATERIAL AND METHODS: In a prospective stroke registry, all patients with large vessel occlusion in anterior circulation admitted within six hours of onset and treated with MT between 2017 and 2020 were retrospectively analysed. RESULTS: A total of 400 patients was evaluated: 267 treated with the MS approach and 133 with the DAS approach. Time from stroke onset to groin puncture was shorter in the MS group. There was a significant difference in 3-month excellent clinical outcomes (mRS 0-1) between these two groups (32.9% of MS patients vs. 22.5% of DAS patients, p < 0.05), but there was no difference if the 3-month endpoint was expressed as mRS ≤ 2 (42.3% of MS vs. 34.5% of DAS patients, p = 0.13). The rate of symptomatic intracranial haemorrhage and mortality was comparable in both groups. CONCLUSIONS: Our study shows that direct admission to a comprehensive stroke centre resulted in more patients achieving excellent treatment outcomes (mRS 0-1). At the same time, the superiority of the MT model over the DAS model in obtaining mRS 0-2 was not unequivocally demonstrated. Further studies are needed to determine the best stroke model for patients potentially eligible for MT.

Stroke patients from rural areas have lower chances for long-term good clinical outcome after mechanical thrombectomy.

BACKGROUND: This study evaluated 3-months clinical outcome after mechanical thrombectomy (MT) in stroke patients transferred to a comprehensive stroke center (CSC) from a rural and urban areas in a Lubelskie province, the third largest province in Poland. MATERIALS AND METHODS: Acute stroke patients with a premorbid modified Rankin scale (mRS) score 0-2 who were admitted within 6 h after stroke onset and treated with MT between 2016 and 2020 were retrospectively analyzed. Patients from rural and urban areas transported directly to CSC were compared regarding the onset-to-groin time, reperfusion rate, symptomatic intracranial hemorrhage (sICH) and favourable clinical outcome (modified Rankin Scale score 0-2) 3-months after MT. RESULTS: A total of 398 patients were analyzed: 179 from rural areas (RA) and 219 from urban areas (UA). There was no significant difference in baseline neurological deficit expressed in The National Institutes of Health Stroke Scale (median 18.4 for RA patients versus 18.1 for UA patients, p = 0.70). Time from stroke onset to groin puncture was significantly shorter in the UA patients (median 197.3 min versus 219.6 min, p = 0.004). There was a significant difference in 3 months favourable clinical outcome between these two groups (31.3% of RA patients versus 42.5% of UA patients, p = 0.021) and full recovery rates (5.6% of RA patients versus 15.0% of UA patients, p = 0.002). The rate of sICH and 3-months mortality was similar in both groups (7.3% of RA patients versus 8.7% of UA patients, p = 0.61% and 21.8% of RA group vs. 22.4% of UA group, p = 0.88, respectively). CONCLUSION: Stroke patients from RA undergoing thrombectomy had worse functional outcome compared to UA patients. Since the benefit of MT is time dependent, urban-rural differences in stroke outcome probably result from the longer time from stroke onset to reperfusion treatment in RA patients.

beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling.

The central levels of endogenous tryptophan metabolite kynurenic acid (KYNA), an antagonist of N-methyl-d-aspartate (NMDA) and alpha7-nicotinic receptors, affect glutamatergic and dopaminergic neurotransmission. Here, we demonstrate that selective agonists of beta(1)-receptors (xamoterol and denopamine), beta(2)-receptors (formoterol and albuterol), alpha- and beta-receptors (epinephrine), 8pCPT-cAMP and 8-Br-cAMP (analogues of cAMP) increase the production of KYNA in rat brain cortical slices and in mixed glial cultures. Neither betaxolol, beta(1)-adrenergic antagonist, nor timolol, a non-selective beta(1,2)-adrenergic antagonist has influenced synthesis of KYNA in both paradigms. In contrast, KT5720, a selective inhibitor of protein kinase A (PKA), strongly reduced KYNA formation in cortical slices (2-10 microM) and in glial cultures (100 nM). beta-adrenergic antagonists and KT5720 prevented the beta-adrenoceptor agonists-induced increases of KYNA synthesis. In vivo, beta-adrenergic agonist clenbuterol (0.1-1.0 mg/kg) increased the cortical endogenous level of KYNA; the effect was blocked with propranolol (10 mg/kg). beta-adrenoceptors agonists, cAMP analogues and KT5720 did not affect directly the activity of KAT I or KAT II measured in partially purified cortical homogenate. In contrast, the exposure of intact cultured glial cells to pCPT-cAMP, 8-Br-cAMP and formoterol has lead to an enhanced action of KATs. These findings demonstrate that beta-adrenoceptor-mediated enhancement of KYNA production is a cAMP- and PKA-dependent event. PKA activity appears to be an essential signal affecting KYNA formation. Described here novel mechanism regulating KYNA availability may be of a potential importance, considering that various stimuli, among them clinically used drugs, activate cAMP/PKA pathway, and thus could counteract the central deficits of KYNA.

Clenbuterol enhances the production of kynurenic acid in brain cortical slices and glial cultures.

The effect of a beta(2)-adrenergic agonist, clenbuterol on the production of a glutamate receptor antagonist, kynurenic acid was studied in vitro. Clenbuterol enhanced the production of kynurenic acid in brain cortical slices (0.1-1.0 mM) and in glial cultures (1-50 muM). Timolol, a non-selective beta-adrenergic antagonist prevented this effect. The presented data indicate a novel mechanism of action of beta(2)-adrenoceptor agonists and suggest that an increased formation of the endogenous glutamate receptor antagonist, kynurenic acid could partially contribute to their neuroprotective activity.

Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism.

We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.

Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients.

KYNA, an antagonist of ionotropic glutamate receptors and alpha7 nicotinic receptors, has been found as well in the brain as in the periphery. The altered metabolism of KYNA, especially its deficiency, can lead to the enhanced glutamate-mediated excitotoxicity, and was suggested to be a factor contributing to the development of neurodegeneration and seizures. Elevated serum concentration of homocysteine is considered to be an independent risk factor of atherosclerosis and is an emerging risk factor of cognitive dysfunction and stroke. In the present study, serum level of KYNA, homocysteine and other biochemical parameters were assessed in patients at early (up to 24 h after infarct) stage of stroke. Serum KYNA and homocysteine levels were similar in control (N = 26) and stroke (N = 24) groups. KYNA level correlated positively with the level of homocysteine in control and in stroke group, with p = 0.018; r = 0.462 and p = 0.027; r = 0.451, respectively. In control group, KYNA correlated positively also with age (p = 0.007; r = 0.514) and with creatinine level (p = 0.002; r = 0.581). In stroke group, serum KYNA correlated positively with creatinine (p = 0.001; r = 0.644) and with urea level (p < 0.001; r = 0.716). Homocysteine level correlated inversely with folate level in control (p = 0.01; r = -0.499) but not in stroke group (p = 0.13; r = -0.317). Serum homocysteine in stroke group correlated positively also with age (p = 0.001; r = 0.6401), and with urea level (p = 0.017; r = 0.4813). Clinical significance of the association between serum KYNA and homocysteine levels requires further investigation.

Endogenous level of kynurenic acid and activities of kynurenine aminotransferases following transient global ischemia in the gerbil hippocampus.

The accumulated data indicate that massively released excitatory amino acids play a major role in mediating the acute ischemic neuronal degeneration. Kynurenic acid (KYNA), the endogenous glutamate receptor antagonist, displaying a particularly high affinity for the glycine-site of N-methyl-D-aspartate (NMDA) receptor, was shown to ameliorate ischemic brain damage and its altered metabolism was implicated in the pathogenesis of neurodegeneration during ischemia/anoxia. Thus, we investigated the effect of transient global ischemia in gerbils on the endogenous levels of KYNA and the activity of its biosynthethic enzymes, kynurenine aminotransferases I (KAT I) and II (KAT II) in the hippocampus, 24 and 72 h after the ischemic episode. The level of KYNA in CA1 area was not altered 24 and 72 h following transient global ischemia (39.7 +/- 3.1 vs. 44.8 +/- 4.2, and 46.3 +/- 4.0 vs. 47.8 +/- 3.9 fmol/mg of tissue). Similarly, the activities of KATs in CA1 area were not changed and reached 1.91 +/- 0.11 vs. 1.8 +/- 0.19 and 1.86 +/- 0.1 vs. 1.7 +/- 0.15 (KAT I), and 0.56 +/- 0.2 vs. 0.43 +/- 0.16 and 0.54 +/- 0.08 vs. 0.55 +/- 0.17 (KAT II) pmol KYNA/mg of tissue/h, respectively. The presented data indicate that KYNA production is preserved in CA1 area of gerbil hippocampus during early stages after ischemic insult.

FK506 attenuates 1-methyl-4-phenylpyridinium- and 3-nitropropionic acid-evoked inhibition of kynurenic acid synthesis in rat cortical slices.

Kynurenic acid (KYNA), the only known endogenous glutamate antagonist, is produced in the brain by kynurenine aminotransferases (KATs) I and II. Mitochondrial toxins, 1-methyl-4-phenylpyridinium (MPP +) and 3-nitropropionic acid (3-NPA), were previously shown to reduce KYNA synthesis via interference with KAT I and II. Data presented here demonstrate that immunophilin ligand, FK506 (10-130 microM), but not CsA (1-50 microM), or ryanodine receptor blocker, dantrolene (1-100 microM), enhances the formation of KYNA in cortical slices. FK506, but not CsA or dantrolene, abolished the inhibition of KYNA synthesis evoked by MPP+ and 3-NPA. None of studied compounds influenced the activity of KAT I and KAT II. FK506 is the first among currently used drugs that might stimulate KYNA synthesis. This effect does not seem to arise from the interference with KATs or calcineurin activity.

L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II.

In the present study the effect of endogenous sulphur-containing amino acids, L-cysteine sulphinate, L-cysteate, L-homocysteine sulphinate and L-homocysteate, on the production of glutamate receptor antagonist, kynurenic acid (KYNA), was evaluated. The experiments comprised the measurements of (a). KYNA synthesis in rat cortical slices and (b). the activity of KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs). All studied compounds reduced KYNA production and inhibited the activity of KAT I and/or KAT II, thus acting most probably intracellularly. L-Cysteine sulphinate in very low, micromolar concentrations selectively affected the activity of KAT II, the enzyme catalyzing approximately 75% of KYNA synthesis in the brain. L-Cysteine sulphinate potency was higher than other studied sulphur-containing amino acids, than L-aspartate, L-glutamate, or any other known KAT II inhibitor. Thus, L-cysteine sulphinate might act as a modulator of KYNA formation in the brain.

1-Methyl-4-phenylpyridinium and 3-nitropropionic acid diminish cortical synthesis of kynurenic acid via interference with kynurenine aminotransferases in rats.

The aim of the present study was to evaluate the effect of mitochondrial inhibitors, 1-methyl-4-phenylpyridinium (MPP(+)) and 3-nitropropionic acid (3-NPA), on the brain production of endogenous glutamate antagonist, kynurenic acid (KYNA). MPP(+) and 3-NPA dose-dependently impaired the synthesis of KYNA in rat cortical slices. Enzymatic studies revealed that MPP(+) inhibits in a concentration-dependent manner the activity of kynurenine aminotransferase II (KAT II), but not the activity of kynurenine aminotransferase I (KAT I). 3-NPA impaired the activity of both enzymes, KAT I and KAT II. Thus, MPP(+)- and 3-NPA-evoked neurotoxicity may be at least partially associated with the depletion of KYNA.

Propranolol and metoprolol enhance the anticonvulsant action of valproate and diazepam against maximal electroshock.

The anticonvulsive potential of classical antiepileptics co-administered with beta-adrenergic receptor antagonists against generalized tonic-clonic seizures was evaluated in the model of maximal electroshock (MES)-induced convulsions. Propranolol, acebutolol, metoprolol and atenolol were tested in the doses not affecting the electroconvulsive threshold. Propranolol and metoprolol lowered the ED(50) of valproate and diazepam. Acebutolol reduced valproate's but not diazepam's ED(50) value. In contrast, hydrophilic atenolol, not penetrating via blood-brain barrier, affected neither the action of valproate nor diazepam. None of the studied drugs changed the protective activity of carbamazepine and phenytoin against MES. beta-blockers per se did not alter the motor performance of mice. Moreover, propranolol and metoprolol did not influence diazepam-evoked impairment of locomotor activity. The free plasma and brain levels of antiepileptic drugs were not affected by beta-blockers. In conclusion, the use of certain beta-adrenoceptor antagonists, such as propranolol and metoprolol, might improve the antiepileptic potential of valproate and diazepam.

The effect of chronic alcohol abuse on gastric and duodenal mucosa.

Alcohol consumed in small quantities is not dangerous for health but if it is drunk in big amounts it has a negative effect on somatic and psychical health. A number of studies have been published on the harmful effect of ethanol on the nervous system, circulation, endocrine and immune systems. Ethyl alcohol can directly damage the mucosa of the alimentary tract. The studies conducted and published so far have estimated acute ethanol damage of gastric mucosa in experimental animals. The views found in literature on the effect of continuous consumption of ethanol on the stomach are differentiated. The purpose of the paper was to provide a morphological and functional analysis of stomach and duodendum in patients who continuously abuse alcohol. Besides, at attempt was made to find the answer to the question whether the changes observed in gastric mucosa point to any connection with the period of alcohol abuse. The study referred to 79 persons: 61 male aged 17-65 who had been chronically drinking alcohol for the period of 5-37 years and 18 persons aged 17-59 (9 male and 9 female) who had never drunk alcohol or who had drunk it only rarely and in small were divided into three groups differing with the period of addiction (I--5-10 years; II--10-20 years; III--over 20 years). Hydrochloric acid secretion in gastric juice was marked and gastroscopy was performed in all the examined patients. Gastroscopy estimated the appearance of the gastric and duodenal mucosa, while biopsy specimens were taken for histological examination from the pyloric area, the body of the stomach and the duodendal bulb. Hydrochloric acid secretion was determined using the Kay's aspiration method. Pentagastrin was used to stimulate gastric secretion. Within the group of 79 patients, gastric mucosa inflammation was observed in all patients chronically drinking alcohol and in 72% patients who were the control. Both groups differed considerably with the degree of progression of the inflammatory process, which was estimated with histological examination. Atrophic gastritis was observed only in patients addicted to alcohol. The appearance of atrophic changes pointed to a close relation with the period of addiction. 13 out of 14 people with this type of inflammation had been drinking alcohol for at least 10 years. The studies did not show any relation existing between the percentage of cases with atrophic inflammation and the kind of drinks or the content of ethanol in them. Examinations concerning the secretory function of the stomach showed lower values of hydrochloric acid secretion, both in basic conditions and after pentagastrin stimulation, in patients addicted to alcohol as compared to the control. The results prove that continuous abuse of alcohol predisposes to atrophic inflammation of the gastric mucosa, and the appearance of this type of inflammatory changes is related to the duration of addiction. The longer the addiction, the lower the secretion of hydrochloric acid is.