Agyi receptor-rendszerek vizsgálata neurológiai kórképekben: speciális és hagyományos autoradiográfiás módszerek alkalmazása Parkinson-kórban, Alzheimer-kórban és az öregedés során = Brain receptor-systems in neurological disorders: special and conventional autoradiographic methods in investigation of Parkinson-disease, Alzheimer-disease and aging

Parkinson kórban a nucleus caudatusban a krónikus l-DOPA kezelésnek betudható csökkent dopamin D2/D3 receptor sűrűség mellett a receptor–G protein jelátvitel kontroll szinten marad, mely funkcionális kompenzáció megnyilvánulása lehet. A gyrus frontalis medialis és gyrus cinguli változatlan dopamin D2/D3 receptor denzitása és szenzitivitása alátámasztja a különböző agyi régiók eltérő mértékű érintettségét és az extrasztriatális tünetek fokozatos megjelenését a Parkinson kór progressziója során. Az új tipusú 125I-SD7015 CB1R ligand nagy érzékenységgel detektálta a CB1R sűrűségbeli különbségeket kontroll és Alzheimer kóros prefrontális minták között. Az Alzheimer kór (AK) korai stádiumaiban tapasztalt szignifikáns CB1R denzitás emelkedés a cannabinoid rendszer neurodegenerációra adott reaktív megnyilvánulása lehet, mely indokolja az AK Braak I-II neuropatológiai stádiumú agyminták kontrolltól különálló csoportba való sorolását. Az Alzheimer kóros prefrontális minták illetve Parkinson kóros putamen és nc caudatus minták esetében, a vizsgált betegségek végső stádiumaiban is ép CB1R populáció alternatív kezelési célpont lehet. Kálium-disztribuciós eljárással egyértelműen elkülöníthető az ischaemiás károsodást szenvedett agyterület az ép régióktól 100 µm vastagságú humán teljes hemispherium metszeteken. A módszer kombinálható a teljes féltekei autoradiográfiával és „térképként” szolgálhat a szomszédos agyterületekkel való összehasonlítás és agyszövet mintavétel során. | Despite the important reduction of dopamine (DA) D2/D3 binding sites in PD nucleus caudate, the increased sensitivity of the remained DA D2/D3 receptors maintains signal transduction effectiveness near to control levels, suggesting functional compensation of DA depletion. In PD middle frontal and cingulated gyrus DA D2/D3 receptor density and sensitivity were on control levels. This supports that dopaminergic neurotransmission of distinct PD brain regions is affected in different extent explaining the gradual appearance of extrastriatal symptoms during PD progression. The novel 125I-SD7015 radioligand (cannabinoid type-1 receptor - CB1R - agonist) detected with high precision CB1R density differences between control and AD prefrontal cortex specimens. In AD Braak I-II sample groups CB1R density was evidently above control levels, suggesting that Braak I-II samples should be studied separately from controls. During the whole progression of AD and PD CB1R densities in prefrontal cortex as well as putamen and nc caudate, respectively, remained on or above control levels showing that CB1R population could serve as alternative target for treatment. Potassium staining method unequivocally differentiated the infarcted brain areas from the intact regions in case of human whole hemisphere sections. This method can be combined with our autoradiographic techniques using whole hemisphere sections; this ’brainmap’ provides base of regional comparison and guide for targeted tissue sampling

Pharmacological and Non-Pharmacological Recanalization Strategies in Acute Ischemic Stroke

According to the guidelines of the European Stroke Organization (ESO) and the American Stroke Association (ASA), acute stroke patients should be managed at stroke units that include well organized pre- and in-hospital care. In ischemic stroke the restoration of blood flow has to occur within a limited time window that is accomplished by fibrinolytic therapy. Newer generation thrombolytic agents (alteplase, pro-urokinase, reteplase, tenecteplase, desmoteplase) have shorter half-life and are more fibrin-specific. Only alteplase has Food and Drug Administration (FDA) approval for the treatment of acute stroke (1996). The National Institute of Neurological Disorders and Stroke (NINDS) trial proved that alteplase was effective in all subtypes of ischemic strokes within the first 3 h. In the European cooperative acute stroke study III trial, intravenous (IV) alteplase therapy was found to be safe and effective (with some restrictions) if applied within the first 3–4.5 h. In middle cerebral artery (MCA) occlusion additional transcranial Doppler insonication may improve the breakdown of the blood clot. According to the ESO and ASA guidelines, intra-arterial (IA) thrombolysis is an option for recanalization within 6 h of MCA occlusion. Further trials on the IA therapy are needed, as previous studies have involved relatively small number of patients (compared to IV trials) and the optimal IA dose of alteplase has not been determined (20–30 mg is used most commonly in 2 h). Patients undergoing combined (IV + IA) thrombolysis had significantly better outcome than the placebo group or the IV therapy alone in the NINDS trial (Interventional Management of Stroke trials). If thrombolysis fails or it is contraindicated, mechanical devices [e.g., mechanical embolus removal in cerebral ischemia (MERCI)- approved in 2004] might be used to remove the occluding clot. Stenting can also be an option in case of acute internal carotid artery occlusion in the future. An intra-aortic balloon was used to increase the collateral blood flow in the Safety and Efficacy of NeuroFlo(™) Technology in Ischemic Stroke trial (results are under evaluation). Currently, there is no approved effective neuroprotective drug

Potential biological markers of atrial fibrillation: a chance to prevent cryptogenic stroke

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Comparison of a New P2Y12 Receptor Specific Platelet Aggregation Test with Other Laboratory Methods in Stroke Patients on Clopidogrel Monotherapy

BACKGROUND: Clinical studies suggest that 10-50% of patients are resistant to clopidogrel therapy. ADP induced platelet aggregation, a widely used test to monitor clopidogrel therapy, is affected by aspirin and is not specific for the P2Y12 receptor inhibited by clopidogrel. OBJECTIVES: To develop a P2Y12-specific platelet aggregation test and to compare it with other methods used for monitoring clopidogrel therapy. PATIENTS/METHODS: Study population included 111 patients with the history of ischemic stroke being on clopidogrel monotherapy and 140 controls. The effect of clopidogrel was tested by a newly developed ADP(PGE1) aggregation test in which prostaglandin E1 treated platelets are used. Results of conventional ADP induced platelet aggregation, VerifyNow P2Y12 assay and ADP(PGE1) aggregation were compared to those obtained by flow cytometric analysis of vasodilator stimulated phosphoprotein (VASP) phosphorylation. Reference intervals for all assays were determined according to the guidelines of Clinical Laboratory Standards Institute. RESULTS: The P2Y12-specificity of ADP(PGE1) test was proven by comparing it with ADP aggregation in the presence of P2Y1 antagonist, adenosine 3', 5'-diphosphate. The method was not influenced by aspirin treatment. Approximately 50% of patients were clopidogrel resistant by conventional ADP aggregation and VerifyNow tests. The ADP(PGE1) method and the VASP phosphorylation assay identified 25.9% and 11.7% of patients as non-responders, respectively. ADP(PGE1) aggregation showed good correlation with VASP phosphorylation and had high diagnostic efficiency. CONCLUSION: The new ADP(PGE1) method is a reliable test for monitoring P2Y12 receptor inhibition by platelet aggregation. As a subset of patients are non-responders, monitoring clopidogrel therapy by adequate methods is essential

Low thrombin generation predicts poor prognosis in ischemic stroke patients after thrombolysis.

Thrombolysis by intravenous recombinant tissue plasminogen activator (rt-PA) is an effective therapy in acute ischemic stroke (AIS). Thrombin generation test (TGT) is a global hemostasis test providing information about the speed and amount of generated thrombin in plasma. Here we aimed to find out whether results of this test before the initiation of thrombolysis might predict outcomes. Study population included 120 consecutive AIS patients, all within 4.5 hours of their symptom onset, who underwent thrombolysis by rt-PA. Blood samples were collected from all patients upon admission and TGT was performed using platelet poor plasma. Clinical data of patients including the NIHSS were registered at admission, day 1 and 7 after therapy. The ASPECT score was assessed using CT images taken before and 24 hours after thrombolysis. Long-term functional outcome was defined 3 months after the event by the modified Rankin Scale. Endogenous Thrombin Potential (ETP) and Peak Thrombin were significantly lower in patients with cardioembolic IS. Symptomatic intracranial hemorrhage (SICH) was found in 6 patients and was significantly associated with low ETP and Peak Thrombin levels. A multiple logistic regression model revealed that an ETP result in the lower quartile is an independent predictor of mortality within the first two weeks (OR: 6.03; 95%CI: 1.2-30.16, p<0.05) and three months after the event (OR: 5.28; 95%CI: 1.27-21.86, p<0.05). Low levels of ETP and Peak Thrombin parameters increase the risk of therapy associated SICH. A low ETP result is an independent predictor of short- and long-term mortality following thrombolysis