Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy

Abstract

Perinatal hypoxic-ischemic brain injury is a major health problem. Adjuvant treatments that improve the neuroprotective effect of the current treatment, therapeutic hypothermia, are urgently needed. The growing knowledge about the complex pathophysiology of hypoxia-ischemia (HI) has led to the discovery of several important targets for neuroprotection. Early interventions should focus on the preservation of energy metabolism, the reduction of glutamate excitotoxicity and oxidative stress, the maintenance of calcium homeostasis, and the prevention of apoptosis. Delayed interventions should promote injury repair. The multiple metabolic changes following HI as well as the metabolic effects of potential treatments can be observed noninvasively by magnetic resonance spectroscopy (MRS). This mini-review provides an overview of the neuroprotective pharmacological agents that have been evaluated with ¹H/³¹P/¹³C MRS. A better understanding of how these agents influence cerebral metabolism and the use of relevant translational MRS biomarkers can guide future clinical trials.

Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

“…The Lac/NAA ratio measured by proton spectroscopy is a bridging biomarker which detects the effect of neuroprotective therapy in animal studies. Tract based spatial statistics with diffusion tensor imaging allows statistically powerful assessment of white matter microstructure, and the separation of small groups of subjects, thus reducing the sample size significantly compared to using visual analysis [8][9][10][11][12][13][14]. The TOBY-Xe study found no evidence of an effect of xenon combined with hypothermia on the cerebral biomarkers and on other outcomes assessed in the neonatal period.…”

Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen

“…Ion flux of sodium (Na + )/potassium (K + ) is altered by the Na + /K + pump dysfunction. In addition, calcium (Ca 2+ ) enters easily to the cell causing membrane depolarization and inhibiting glutamate storage inside the cell, being therefore accumulated in the extracellular space [18]. The second phase of the injury is caused by the recovery of blood flow and the reestablishment of brain metabolism, which are characterized by an inflammatory response, excitotoxicity and oxidative stress.…”

“…TH is the unique treatment available after resuscitation from moderate-to-severe perinatal HI. It should be started as soon as possible, at least within 6 h after birth, and continued for 72 h [18]. Using TH before the onset of the secondary energy failure prevents the development of cytotoxic edema, cell death and brain damage [18,122].…”

“…It has been shown that mild hypothermia could reduce or inhibit secondary impaired oxidative phosphorylation, augmenting ATP and correcting Protein C reactive (PCr) levels after HI [18]. TH protects the brain by reducing brain metabolism in almost 5% for every degree of temperature lowering [122].…”

“…TH protects the brain by reducing brain metabolism in almost 5% for every degree of temperature lowering [122]. Reducing cerebral metabolism provokes the attenuation of oxidative stress, excitotoxicity, inflammation, cell death pathways and the accumulation of essential amino acids due to the delay in the depolarization [18,122]. The efficacy of TH can be clinically and experimentally tested with the use of prognostic 1H magnetic resonance spectroscopy (MRS) biomarkers [18].…”