Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death.

نویسندگان

  • Patrick G Sullivan
  • Celine Dubé
  • Kristina Dorenbos
  • Oswald Steward
  • Tallie Z Baram
چکیده

Excitotoxic cell death is the fundamental process responsible for many human neurodegenerative disorders, yet the basic mechanisms involved are not fully understood. Here, we exploited the fact that the immature brain is remarkably resistant to seizure-induced excitotoxic cell death and examined the underlying protective mechanisms. We found that, unlike in the adult, seizures do not increase the formation of reactive oxygen species or result in mitochondrial dysfunction in neonatal brain, because of high levels of the mitochondrial uncoupling protein (UCP2). UCP2 expression and function were basally increased in neonatal brain by the fat-rich diet of maternal milk, and substituting a low-fat diet reduced UCP2, restored mitochondrial coupling, and permitted seizure-induced neuronal injury. Thus, modulation of UCP2 expression and function by dietary fat protects neonatal neurons from excitotoxicity by preventing mitochondrial dysfunction. This mechanism offers novel neuroprotective strategies for individuals, greater than 1% of the world's population, who are affected by seizures.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death

Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibi...

متن کامل

The emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury

Traumatic brain injury (TBI) is a multifaceted disease with intrinsically complex heterogeneity and remains a significant clinical challenge to manage. TBI model systems have demonstrated many mechanisms that contribute to brain parenchymal cell death, including glutamate and calcium toxicity, oxidative stress, inflammation, and mitochondrial dysfunction. Mitochondria are critically regulated b...

متن کامل

Mitochondrial dysfunction contributes to cell death following traumatic brain injury in adult and immature animals.

Secondary injury following traumatic brain injury (TBI) is characterized by a variety of pathophysiologic cascades. Many of these cascades can have significant detrimental effects on cerebral mitochondria. These include exposure of neurons to excitotoxic levels of excitatory neurotransmitters with intracellular calcium influx, generation of reactive oxygen species, and production of peptides th...

متن کامل

Change of Nurr1 expression in mouse hippocampal CA3 region following excitotoxic neuronal damage

Objective(s): Nuclear receptor-related protein 1 (Nurr1), one of immediate-early genes, is a member of orphan nuclear receptor family. The aim of this study was to investigate the time-dependent change of Nurr1 protein expression in the mouse hippocampal CA3 region following kainic acid (KA)-induced excitotoxic neuronal damage.Materials and Methods:</...

متن کامل

Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning.

The mitochondrial uncoupling protein (UCP2) is expressed in selected regions of the brain. Here we demonstrate that up-regulation of UCP2 is part of a neuroprotective set of responses to various cellular stresses in vitro and in vivo. PC12 cells, when transfected with UCP2, were protected against free radical-induced cell death. Seizure activity was associated with elevated UCP2 levels and mito...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Annals of neurology

دوره 53 6  شماره 

صفحات  -

تاریخ انتشار 2003