Thiamine as a Possible Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

On the basis that similar biochemical and histological sequences of events occur in the brain during thiamine deficiency and hypoxia/ischemia related brain damage, we have planned this review to discuss the possible therapeutic role of thiamine and its derivatives in the management of neonatal hypoxic-ischemic encephalopathy (HIE). Among the many benefits, thiamine per se as antioxidant, given intravenously (IV) at high doses, defined as dosage greater than 100 mg IV daily, should counteract the damaging effects of reactive oxygen and nitrogen species in the brain, including the reaction of peroxynitrite with the tyrosine residues of the major enzymes involved in intracellular glucose metabolism, which plays a key pathophysiological role in HIE in neonates. Accordingly, it is conceivable that, in neonatal HIE, the blockade of intracellular progressive oxidative stress and the rescue of mitochondrial function mediated by thiamine and its derivatives can lead to a definite neuroprotective effect. Because therapeutic hypothermia and thiamine may both act on the latent period of HIE damage, a synergistic effect of these therapeutic strategies is likely. Thiamine treatment may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment.

New Therapeutic Paradigms in Neonatal Hypoxic–Ischemic Encephalopathy

“…N eonatal hypoxic-ischemic encephalopathy (HIE) is a serious neurological syndrome due to severe perinatal asphyxia, which results in deprivation of blood supply, glucose, and oxygen to the brain. 1 In term and near-term infants, it contributes about 700 000 deaths per year worldwide, affecting 1−3 per 1000 live births in developed countries and increasing to 26 per 1000 in the Global North/South world. 2 Moreover, among surviving neonates with moderate-to-severe HIE, despite the treatment with therapeutic hypothermia (TH), the current standard of care for this encephalopathy, about 25% still suffer significant neurological sequelae such as infantile cerebral palsy, epilepsy, and learning disabilities.…”

“…2 Moreover, among surviving neonates with moderate-to-severe HIE, despite the treatment with therapeutic hypothermia (TH), the current standard of care for this encephalopathy, about 25% still suffer significant neurological sequelae such as infantile cerebral palsy, epilepsy, and learning disabilities. 1,2 Accordingly, reducing the morbidity and mortality associated with neonatal HIE should be a public health imperative among all populations. In particular, the development of innovative, molecularly targeted, neuroprotective strategies that might improve the outcomes for these neonates seems necessary and very promising.…”

“…1 Among them, most interventions have been evaluated in preclinical studies only or also in small clinical trials. 1 Few interventions, namely, TH alone and the noble gas xenon and erythropoietin given in conjunction with TH, have been evaluated in multicenter, randomized, controlled clinical trials. Importantly, moderate TH has demonstrated significant beneficial effect when compared with controls.…”

“…Importantly, moderate TH has demonstrated significant beneficial effect when compared with controls. Instead neither xenon nor erythropoietin has shown any additional benefit when given in conjunction with TH, 1,3 further confirmation of the critical need to search for additional, potentially useful therapeutic paradigms in neonatal HIE.…”

“…5 After perinatal asphyxia, HIE damage occurs gradually and progressively in distinct phases, acute insult, latent phase, and secondary and tertiary phases. 1 Of note, a large number of experimental and clinical studies document that in HIE the effectiveness of treatments, such as TH, the use of KBs and thiamine, is strictly related to the promptness of their application, and the earlier they are used the better is the long-term outcome. 1 In particular, treatments should be given in the time frame of the initial 6 h after the acute insult, in the latent phase, the so-called stage of "reversible biochemical lesion", when the correct use of an effective treatment should be able to induce a potent, long-lasting neuroprotection, decreasing dramatically the likelihood of permanent neurological sequelae or a fatal outcome.…”