scholarly journals Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression

2011 ◽  
Vol 31 (7) ◽  
pp. 1588-1598 ◽  
Author(s):  
Henning Piilgaard ◽  
Brent M Witgen ◽  
Peter Rasmussen ◽  
Martin Lauritzen
Keyword(s):  
Cyclosporine A ◽  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Mitochondrial Permeability Transition ◽  
Neurovascular Coupling ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Doppler Flowmetry ◽  
Electrocortical Activity

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca2+, and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis that cyclosporine A (CsA), which blocks both mPTP and CaN, ameliorates the persistent reduction of cerebral blood flow (CBF), impaired vascular reactivity, and a persistent rise in the cerebral metabolic rate of oxygen (CMRO2) following CSD. In addition to CsA, we used the specific mPTP blocker NIM811 and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO2, and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD; the rise in CMRO2 was unchanged. Our data suggest that blockade of mPTP formation and CaN activation may prevent persistent CBF reduction and vascular dysfunction after CSD.

scholarly journals Persistent Increase in Oxygen Consumption and Impaired Neurovascular Coupling after Spreading Depression in Rat Neocortex

2009 ◽  
Vol 29 (9) ◽  
pp. 1517-1527 ◽  
Author(s):  
Henning Piilgaard ◽  
Martin Lauritzen
Keyword(s):  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Acute Hypoxia ◽  
Ion Homeostasis ◽  
Neurovascular Coupling ◽  
Doppler Flowmetry ◽  
Neurometabolic Coupling ◽  
Rat Neocortex ◽  
Cortical Electrical Activity

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is the mechanism of migraine, and involved in progressive neuronal injury in stroke and head trauma. Here we tested the hypothesis that single episodes of CSD induced acute hypoxia, and prolonged impairment of neurovascular and neurometabolic coupling. Cortical spreading depression was induced in rat frontal cortex, whereas cortical electrical activity and local field potentials (LFPs) were recorded by glass microelectrodes, cerebral blood flow (CBF) by laser—Doppler flowmetry, and tissue oxygen tension (tpO2) with Polarographic microelectrodes. Cortical spreading depression increased cerebral metabolic rate of oxygen (CMRO2) by 71% ± 6.7% and CBF by 238% ± 48.1% for 1 to 2 mins. For the following 2 h, basal tpO2 and CBF were reduced whereas basal CMRO2 was persistently elevated by 8.1% ± 2.9%. In addition, within first hour after CSD we found impaired neurovascular coupling (LFP versus CBF), whereas neurometabolic coupling (LFP versus CMRO2) remained unaffected. Impaired neurovascular coupling was explained by both reduced vascular reactivity and suppressed function of cortical inhibitory interneurons. The protracted effects of CSD on basal CMRO2 and neurovascular coupling may contribute to cellular dysfunction in patients with migraine and acutely injured cerebral cortex.

scholarly journals On the Mechanism(s) of Membrane Permeability Transition in Liver Mitochondria of Lamprey,Lampetra fluviatilis L.: Insights from Cadmium

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Elena A. Belyaeva ◽  
Larisa V. Emelyanova ◽  
Sergey M. Korotkov ◽  
Irina V. Brailovskaya ◽  
Margarita V. Savina
Keyword(s):  
Membrane Permeability ◽  
Cyclosporine A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Nitrate Medium ◽  
Lampetra Fluviatilis ◽  
Mitochondrial Permeability

Previously we have shown that opening of the mitochondrial permeability transition pore in its low conductance state is the case in hepatocytes of the Baltic lamprey (Lampetra fluviatilis L.) during reversible metabolic depression taking place in the period of its prespawning migration when the exogenous feeding is switched off. The depression is observed in the last year of the lamprey life cycle and is conditioned by reversible mitochondrial dysfunction (mitochondrial uncoupling in winter and coupling in spring). To further elucidate the mechanism(s) of induction of the mitochondrial permeability transition pore in the lamprey liver, we used Cd2+and Ca2+plus Pias the pore inducers. We found that Ca2+plus Piinduced the high-amplitude swelling of the isolated “winter” mitochondria both in isotonic sucrose and ammonium nitrate medium while both low and high Cd2+did not produce the mitochondrial swelling in these media. Low Cd2+enhanced the inhibition of basal respiration rate of the “winter” mitochondria energized by NAD-dependent substrates whereas the same concentrations of the heavy metal evoked its partial stimulation on FAD-dependent substrates. The above changes produced by Cd2+or Ca2+plus Piin the “winter” mitochondria were only weakly (if so) sensitive to cyclosporine A (a potent pharmacological desensitizer of the nonselective pore) added alone and they were not sensitive to dithiothreitol (a dithiol reducing agent). Under monitoring of the transmembrane potential of the “spring” lamprey liver mitochondria, we revealed that Cd2+produced its decrease on both types of the respiratory substrates used that was strongly hampered by cyclosporine A, and the membrane potential was partially restored by dithiothreitol. The effects of different membrane permeability modulators on the lamprey liver mitochondria function and the seasonal changes in their action are discussed.

scholarly journals Tissue Specific Sensitivity of Mitochondrial Permeability Transition Pore to Ca2+ Ions

2009 ◽  
Vol 52 (2) ◽  
pp. 69-72 ◽  
Author(s):  
René Endlicher ◽  
Pavla Křiváková ◽  
Halka Lotková ◽  
Marie Milerová ◽  
Zdeněk Drahota ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Heart Mitochondria ◽  
Cell Protection ◽  
Tissue Specific ◽  
Mitochondrial Permeability

Ca2+-induced opening of the mitochondrial permeability transition pore (MPTP) is involved in induction of apoptotic and necrotic processes. We studied sensitivity of MPTP to calcium using the model of Ca2+-induced, cyclosporine A-sensitive mitochondrial swelling. Presented data indicate that the extent of mitochondrial swelling (dA520/4 min) induced by addition of 25 μM Ca2+ is seven-fold higher in liver than in heart mitochondria (0.564 ± 0.08/0.077± 0.01). The extent of swelling induced by 100 μM Ca2+ was in liver tree times higher than in heart mitochondria (0.508±0.05/ 0.173±0.02). Cyclosporine A sensitivity showed that opening of the MPTP is involved. We may thus conclude that especially at low Ca2+ concentration heart mitochondria are more resistant to damaging effect of Ca2+ than liver mitochondria. These finding thus support hypothesis that there exist tissue specific strategies of cell protection against induction of the apoptotic and necrotic processes.

Arginine-nitric oxide pathway and cerebrovascular regulation in cortical spreading depression

1995 ◽  
Vol 269 (1) ◽  
pp. H23-H29 ◽  
Author(s):  
M. Fabricius ◽  
N. Akgoren ◽  
M. Lauritzen
Keyword(s):  
Nitric Oxide ◽  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Clinical Importance ◽  
Receptor Activation ◽  
Marked Rise ◽  
Doppler Flowmetry ◽  
Pial Arterioles ◽  
Cerebrovascular Regulation

Nerve cells release nitric oxide (NO) in response to activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. We explored the hypothesis that NO influences the changes of cerebral blood flow (CBF) during cortical spreading depression (CSD), which is known to be associated with NMDA receptor activation. CBF was monitored in parietal cortex by laser-Doppler flowmetry in halothane-anesthetized rats. Under control conditions, CSD induced regular changes of CBF, which consisted of four phases: a brief hypoperfusion before the direct current (DC) shift; a marked CBF rise during the DC shift; followed by a smaller, but protracted increase of CBF; and a prolonged CBF reduction (the oligemia). NO synthase inhibition by intravenous and/or topical application of NG-nitro-L-arginine enhanced the brief initial hypoperfusion, but the CBF increases and the oligemia were unchanged. L-Arginine prevented the development of the prolonged oligemia after CSD but had no influence on the marked rise of CBF during CSD. Animals treated with L-arginine recovered the reduced vascular reactivity to hypercapnia after CSD much faster than control rats. Functional denervation of cortical and pial arterioles by tetrodotoxin accentuated the pre-CSD hypoperfusion and the oligemia but did not affect the CBF increases. The results suggest that NO is important for the changes of cerebrovascular regulation following CSD. The observations may have clinical importance, since CBF changes during migraine may be triggered by CSD.

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