Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes: consequences for neuronal excitability

Abstract

This chapter discusses that hyperammonemia resulting from liver failure, reye syndrome, or congenital urea cycle disorders leads invariably to severe neurological impairment. Neuropathologic studies in hyperammonemia reveal selective changes of astrocyte morphology consisting of brain edema or Alzheimer Type II astrocytosis. Exposure of astrocytes to increased concentrations of ammonia results in alteration in expression of genes coding for key astrocytic proteins, including glial fibrillary acidic protein, glucose and amino acid transporters, and peripheral-type benzodiazepine receptor (PTBR).The chapter reviews that brain concentrations of putative endogenous ligands for PTBR, including diazepam binding inhibitor (DBI) and its processing product octadecaneuropeptide, are increased in these disorders. The activation of PTBR in brain by neuronally released DBI, resulting in the formation of neurosteroids with potent neuroactive properties, represents a further example of altered astrocyte–neuronal trafficking, a phenomenon which is consistently encountered in hyperammonemic disorders. Pharmacological manipulation of PTBR and/or its associated neurosteroid synthesis pathways may afford novel therapeutic approaches to the management and treatment of the cerebral consequences of hyperammonemia.