N‐methyl‐D‐aspartate (NMDA) increases cortical blood flow in part by evoking cortical spreading depression (CSD) in insulin resistant Zucker rats

These experiments were designed to investigate a possible mechanism linking the phenomenon of cortical spreading depression with activation of the trigeminal sensory system in migraine. Blood flow in the cortex and middle meningeal artery was measured in cats before and during propagation of a wave of cortical spreading depression, initiated by cortical pin-prick, This caused a transient propagated increase in cortical blood flow. Cortical spreading depression was accompanied by a decrease in blood flow in the middle meningeal artery, sometimes to very low levels. The results suggest that the pain of migraine could arise from dural ischemia induced by cortical spreading depression.

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Spreading depression reversibly impairs autoregulation of cortical blood flow

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.4.r1136 ◽

1994 ◽

Vol 266 (4) ◽

pp. R1136-R1140 ◽

Cited By ~ 2

Author(s):

G. Florence ◽

G. Bonvento ◽

R. Charbonne ◽

J. Seylaz

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Laser Doppler Flowmetry ◽

Initial Phase ◽

Cortical Spreading Depression ◽

Time Course ◽

Spreading Depression ◽

Doppler Flowmetry ◽

Cortical Blood Flow ◽

Before And After

The experiment examines whether the mechanisms responsible for the autoregulation of cerebral blood flow (CBF) in response to hypotension were affected during the initial phase of cortical spreading depression (CSD). CSD was induced by a cortical pinprick in anesthetized rabbits, and CBF was measured by laser-Doppler flowmetry through a chronically implanted Plexiglas window. The reactivity to CO2 and papaverine was also studied before and after CSD. Fifteen minutes after CSD, autoregulatory vasodilation was reduced (P < 0.01). This impairment was reversible, since the autoregulatory response was restored 35 min after CSD. The time course of the reactivity to papaverine after CSD paralleled the autoregulatory response, with a significant correlation between the two reactivities (r = 0.47; P < 0.01). Conversely, the reactivity to CO2 was significantly reduced after CSD (P < 0.001) and remained affected for at least 95 min. We conclude that the mechanisms underlying autoregulation are transiently disturbed by CSD and that these mechanisms are not mediated by an accumulation of CO2 but seem instead to be related to an increase in adenosine 3',5'-cyclic monophosphate concentration.

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PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16645595 ◽

2016 ◽

Vol 37 (5) ◽

pp. 1820-1828 ◽

Cited By ~ 16

Author(s):

Krzysztof Kucharz ◽

Ida Søndergaard Rasmussen ◽

Anders Bach ◽

Kristian Strømgaard ◽

Martin Lauritzen

Keyword(s):

Blood Flow ◽

Nmda Receptors ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Neuronal Excitability ◽

Synaptic Activity ◽

Cortical Function ◽

Neuroprotective Effects ◽

Cortical Blood Flow

Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat- N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat- N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat- N-dimer suppressed stimulation-evoked synaptic activity by 2–20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat- N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2. We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarization wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

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Hypoxia and Hypotension Transform the Blood Flow Response to Cortical Spreading Depression from Hyperemia into Hypoperfusion in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.35 ◽

2008 ◽

Vol 28 (7) ◽

pp. 1369-1376 ◽

Cited By ~ 56

Author(s):

Inna Sukhotinsky ◽

Ergin Dilekoz ◽

Michael A Moskowitz ◽

Cenk Ayata

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Ischemic Penumbra ◽

Doppler Flowmetry ◽

Blood Flow Response ◽

Flow Response ◽

Normal Rat ◽

Cortex Cérébral

Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74 ± 7%) occasionally preceded by a small hypoperfusion (−4 ± 2%). Both hypoxia ( pO2 45 ± 3 mm Hg) and hypotension (blood pressure 42 ± 2 mm Hg) independently augmented this initial hypoperfusion (−14 ± 2% normoxic hypotension; −16 ± 6% hypoxic normotension; −21 ± 5% hypoxic hypotension) and diminished the magnitude of hyperemia (44 ± 10% normoxic hypotension; 43 ± 9% hypoxic normotension; 27 ± 6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs.

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