Spreading Depression and Hypoxic Spreading Depression-Like Depolarization Dept. of Physiology, ZUSM LHW

INTRODUCTION Spreading depression (SD) is a striking and highly reproducible response of the gray matter of the central nervous system

SD & HSD INTRODUCTION Characteristics of SD At the core of SD is a rapid and nearly complete depolarization of a sizable population of brain cells With massive redistribution of ions between intracellular and extracellular compartments Evolves as a regenerative, “all-or-none” type process Propagates in the manner of a wave through gray matter

SD & HSD INTRODUCTION Normoxic SD can be triggered by high-frequency electrical pulses or direct current mechanical stimuli such as pressure on or puncture of the cortex alkaline pH low osmolarity a variety of chemicals

SD & HSD INTRODUCTION

Hypoxic SD (HSD) A similar response to SD occurs in cerebral gray matter a few minutes after interruption of the blood flow or of the supply of oxygen

SD & HSD INTRODUCTION

SIMILARITIES BETWEEN SD AND HSD The waveform of the  V o is essentially identical in SD and HSD, provided that oxygenation is restored shortly after the onset of HSD The  V o propagate at similar velocities in the tissue during SD and HSD

SD & HSD SIMILARITIES BETWEEN SD AND HSD Ion concentrations change in identical fashion Neurons lose K + and organic anions, including glutamate, to the interstitial fluid Na +, Ca 2+, and Cl – flow into neurons

SD & HSD SIMILARITIES BETWEEN SD AND HSD Interstitial space shrinks to the same degree The reduction in membrane potential and input resistance of neurons and glial cells are indistinguishable in the two processes

DIFFERENCES BETWEEN SD AND HSD Depolarization in SD is self-limiting, but in HSD, Vm and excitability recover only if oxygen is restored soon after the onset of depolarization

SD & HSD DIFFERENCES BETWEEN SD AND HSD The timing of synaptic failure occurs minutes before the onset of HSD, whereas in normoxic SD synapses continue to function until depolarization inactivates ion channels

SD & HSD DIFFERENCES BETWEEN SD AND HSD In the pharmacology of the two conditions NMDA antagonist drugs are more effective against SD than against HSD While TTX postpones HSD more powerfully than SD

SD, HSD, AND NEURON SURVIVAL In the hippocampus those neurons that develop HSD early are the most sensitive to injury by hypoxia It is not the depolarization itself that damages neurons Nor is it the calcium itself that kills cells

SD & HSD SD, HSD, AND NEURON SURVIVAL Normoxic SD episodes are harmless But if neurons are forced to remain depolarized for extended periods, they do not regain function afterward SD can also cause damage in cells with compromised energy supply

SD AND HYPOXIA TOLERANCE Previous normoxic SD imparts a measure of “cross-tolerance” against subsequent cerebral hypoxia or ischemia and excitotoxic injury The SD waves that emanate from an established ischemic focus and spread into the penumbral surround cause the extension of the infarcted area

GLUCOSE, pH, HSD, AND SURVIVAL AFTER TRANSIENT ISCHEMIA The eventual outcome is worse for diabetics than for other patients Acidosis of the degree experienced by diabetic patients does not injure brain tissue itself, and the damage is probably done to blood vessels, or it is secondary to systemic effects Hyperglycemia postpones HSD

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