Evaluation of trigger factors of acute encephalopathy in glutaric aciduria type I: fever and tumour necrosis factor-alpha.

Abstract

It is well known that acute encephalopathic crises in glutaric aciduria type I (GA I; McKusick 231670) often precipitate from acute intercurrent illness, e.g. acute febrile infections, leading to an irreversible excitotoxic neuronal damage in striatum and cortex via activation of NMDA receptors (Hoffmann et al 1996; Kolker et al 1999). The exact influence of temperature and inflammatory cytokines (e.g. tumour necrosis factor-a (TNF-a)) on the extent of neuronal damage in GA I has hitherto been unclear. TNF-α is a potent neuromodulator in the central nervous system (Pan et al 1997). Results of previous studies with TNF-a are conflicting, revealing a potentiating effect of TNF-a on glutamate neurotoxicity (Chao and Hu 1994), as well as reduced intracellular Ca 2+ responses to excitotoxic amino acids via activation of NFκB (Furukawa and Mattson 1998). Brain temperature influences many neuronal processes, e.g. neurotransmitter release, requirement for energy, as well as activity of different intracellular mediators. It has previously been shown that brain temperature modulates the outcome of ischaemic brain injury (Ginsberg 1998). We therefore investigated the influence of temperature and TNF-a on neuronal damage induced by 3-hydroxyglutaric (3-OH-GA) and glutaric acids (GA) in vitro.