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Joint Meeting of the Federation of European Physiological Societies and the Austrian Physiological Society

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09/13/2017 - Hall A | 3:00pm - 5:00pm 
Symposium 3: Cerebrovascular disorders: Pathophysiological and pharmacological approaches

Organizer: E. Agar (Samsun, Turkey); Co-chair: E. Fabbri (Bologna, Italy)

Post-acute effects of CDNF and MANF on brain plasticity and repair
*Ertugrul Kilic1
1 Istanbul Medipol University, Physiology, Istanbul, Turkey
Abstract text :

Ischemic- stroke remains among the leading cause of serious motor disabilities in developed countries. Initial hemiparesis affects 80–90% of patients; however, 45–60% still exhibit motor deficits in the post-acute stroke phase. Post-ischaemic endogenous responses of the central nervous system go in line with an enhanced responsiveness to rehabilitative and plasticity-promoting treatments, such as growth factors, opening a time window in which brain repair mechanisms may be reactivated successfully. Therefore, to stimulate post-ischemic functional recovery, promoting perilesional tissue remodelling and pyramidal tract plasticity are major challenges of post-acute ischemic stroke. In this context, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) differ from the other known growth factors by their smaller size of ~18kDa and their unique amino acid sequences. These differences indicate that they utilize distinct signaling pathways and hence, they may exert different effects than other known factors. They are currently among the most promising molecules for the treatment for Parkinson"s disease besides neuroprotective activity in acute ischemic- stroke. In the present talk, effects of CDNF and MANF on inflammation, neurogenesis, angiogenesis, post-ischemic functional recovery, perilesional tissue remodelling and pyramidal tract plasticity will be reviewed. These studies were supported by grant of The Scientific and Technological Research Council of Turkey (TUBITAK). Project number: 114S402.

Pericytes as an important target in Stroke and other Neurological Diseases' Pathophysiology
*Yasemin Gürsoy-Özdemir1
1 Koç University, Neurology, İstanbul, Turkey
Abstract text :

The role of microcirculation and cells of blood-brain barrier in stroke pathophysiology is an important issue and pericytes are one of the important players. Brain pericytes have many important roles in blood flow regulation and understanding their physiological properties and contribution to neurological disease mechanisms is important for development of novel theurapeutic options.

Pericytes are the cells found around the abluminal side of endothelium and located in between microvascular endothelia and basal lamina-astrocytes. These cells are found mainly at the precapillary arterioles, the capillaries and the postcapillary venules. They have contractile properties and regulate the blood flow at the microcirculation via constricting or dilating capillaries, precapillary arteriols and post capillary venules. They can be considered as continuation of arterial smooth muscle cells and can regulate blood flow according to neuronal needs and hence functional connection can be established. Other than blood flow regulation, they have other several important roles like maintenance of blood-brain barrier.

Pericytes are especially important for providing adequate microcirculatory supply according to needs of neuronal tissue and form one of the functionally important part of BBB and take role in neurovascular coupling. They perform this regulation through their contractile properties, playing important roles in acute injuries like stroke as well as chronic neurological diseases. Understanding the role and disease producing mechanisms of neurovascular unit elements in different neurological conditions will provide novel targets for future treatments.

Neuroregenerative approaches using neural progenitor cells to counteract cerebral ischemia
*Thorsten R.  Döppner1
1 University Medical Center Goettingen, Neurology, Goettingen, Germany
Abstract text :

Treatment of cerebral ischemia (i.e., ischemic stroke) has made tremendous progress in recent years. With systemic (intravenous) thrombolysis being a well-established therapeutic means to counter ischemic stroke, endovascular treatment has become an additional and powerful tool for physicians as well. Yet, a majority of patients does not qualify for either treatment paradigms because of potential side effects and narrow time window. As such, additional treatment paradigms are urgently needed. With neuroprotective approaches having failed so far, the focus of experimental stroke research has switched towards neuroregenerative strategies. Endogenous neurogenesis persists in the adult mammalian brain, although it might contribute little to neurological recovery as both survival and differentiation rates of new-born neural progenitor cells (NPCs) are low. Yet, endogenous neurogenesis can be stimulated by various means, among which the transplantation of ectopic NPCs is feasible. The latter, however, need to have an appropriate extracellular milieu in order to exert their protective and regenerative potential. Modulation of the post-stroke extracellular milieu is achieved by various experimental strategies. We herein focus on the introduction of post-stroke conditioning, i.e., the induction of an additional non-injurious ischemia of either the brain (cerebral post-conditioning) or the periphery (remote post-conditioning). Pro-injurious and rescue pathways will be analyzed after post-conditioning in stroke mice, followed by a transplantation of NPCs derived from the subventricular zone of the lateral ventricles. Finally, the impact of the combined therapeutic approach after both post-conditioning and NPC transplantation on post-stroke neurological recovery will be analyzed in mice.

S03-4 (O)
Internal carotid artery blood flow response to isometric handgrip and head-down tilt in healthy volunteers.
*Maria Skytioti1, Signe Søvik2, Maja Elstad1
1 Institute of Basic Medical sciences,UiO, Physiology, Oslo, Norway
2 Akershus University Hospital, , Oslo, Norway
Abstract text :

Questions          We examined internal carotid artery (ICA) blood flow response to isometric exercise in the horizontal position and in head-down tilt position (HDT). During HDT, the increased central blood volume results in an increase in CO. Handgrip maneuver increases MAP through the exercise pressor reflex.

Methods             Blood velocity in ICA (Doppler ultrasound) was recorded during rest and handgrip (30% of maximal voluntary contraction) randomized between horizontal and HDT by 10° in 13 healthy volunteers. Heart rate, MAP, CO, ETCO2 were recorded. ICA blood flow was calculated beat-by-beat from velocity, the diameter of ICA, angle of insonation and instantaneous heart rate. Wilcoxon signed rank test evaluated the differences between conditions.

Results                Results (median, 95% CI) show that ICA blood flow was preserved from rest (260, 189-304ml/min) to handgrip (282, 200-323 ml/min) in the horizontal position, from rest to HDT (265, 190-287 ml/min) and to the combined handgrip and HDT (258, 182-295 ml/min). On the contrary, CO, MAP and HR increased significantly from rest to handgrip (CO: 15%, (p<0.001), MAP: 16%, (p<0.001), HR: 10%, (p<0.001)) and to HDT handgrip (CO: 23%, (p<0.001), MAP: 17%, (p<0.001), HR: 15%, (p<0.001)). ETCO2 did not change between conditions.

Conclusions       ICA blood flow did not change with static exercise in the horizontal position nor during HDT (elevated CO) despite the significant increase in MAP. Sympathetic activation through the exercise pressor reflex may induce cerebral vasoconstriction which prevents cerebral hyperemia. Our findings suggest an intact static cerebral autoregulation which maintained cerebral blood flow despite the simultaneous increases in MAP and CO.

S03-5 (O)
The role of angiotensin -1 receptors in vasodilator responses of middle cerebral arteries in Sprague-Dawley rats
*Ines Drenjancevic1, Anita Cosic1, Ivana Jukic1, Zrinka Mihaljevic1, Ana Stupin1
1 Faculty of Medicine University of Osijek, Physiology and Immunology, Osijek, Croatia
Abstract text :

Questions: This study aimed to evaluate the role of angiotensin 1 receptors in endothelium-dependant (flow-induced dilation (FID) and acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside; SNP) vasodilator responses in cerebral resistance vessels of Sprague-Dawley rats. Additionally, the effects of AT-1R blockade on oxidative status and the role of oxidative stress on vasodilator responses was examined.

Methods: Healthy male Sprague-Dawley rats (N=6-7 per group) were fed low salt (0.4%NaCl; LS group) or LS losartan (AT-1R blocker; losartan 40 mg/day in water ad lib) for 7 days. Middle cerebral arteries" responses to ACh (10-6M), SNP (10-6M) and FID (FID established by increases in pressure gradient (Δ10-Δ100 mmHg)) were studied in absence/presence of superoxide scavenger, TEMPOL (100 μmol/l). Plasma angiotensin II (ANG II) levels were measured by ELISA and plasma antioxidant capacity (FRAP) and lipid peroxidation level (TBARS) were measured by spectrophotometry. Mean arterial blood pressure (MAP) was also measured.

Results: LS losartan group exhibited significantly decreased vasodilation in response to ACh and FID, while SNP-induced dilation was preserved in both groups. FID was restored by addition of TEMPOL in chamber bath. LS losartan group had significantly higher ANGII plasma concentration, higher TBARS and lower MAP compared to LS group. FRAP was similar between the groups.

Conclusions: Increased oxidative stress may be underlying impaired endothelium-dependant dilation responses. Results suggest important role of ANG II in maintaining arterial relaxation responses via AT-1 receptor activation in physiological conditions. Support: Croatian Science Fundation grant #IP-2014-09-6380.