References

178 A. Fait, A. Yellin, H. Fromm
(Mamelak 1989, 1997; Boyd et al. 1990; Kolin et al. 1993). French scientist
and philosopher Laborit reported on anticonvulsive effects of GHB (Laborit
1964). Laborit (1973) suggested that GHB causes the nervous system
to catabolize glucose mainly through the pentose shunt in glial cells, thus
utilizing less oxygen, with consequential decrease in reactive oxygen intermediates
(ROI), and the production of reducing power to counteract the
high daytime glycolytic-mitochondrial metabolic activity (Genova et al.
2004).
12.3.2
SSADH Inborn Deficiency: the Dark Side of GHB
In the past 20 years, interest has grown toward GHB in connection to a rare
inborn error of GABA catabolism in humans due to SSADH deficiency,
an autosomal-recessive inherited disorder, of which there are likely less
than 400 patients worldwide (Gupta et al. 2003). This pathology, which
manifests physiologically as GHB–aciduria, has at least two neuroactive
species, GABA and GHB. The understanding of the possible mechanisms
behind this pathology has been aided by the study of murine knockout
models. The complete absence of SSADH enzyme activity in neuronal
andperipheraltissueleadstothebirthofssadh mice characterized by
a phenotype reminiscent of the human disease (Gupta et al. 2003). The
pathological characters include neurological impairment and growth retardation,
ataxia, and seizures, which eventually lead to 100%mortality, in
addition to a severe GHB accumulation (35–40-fold) and a minor increase
in GABA (2–3-fold) in the mice urine, brain, and peripheral brain extracts.
An intriguing reduction of glutamine was also reported. In contrast, other
metabolites linked to the GABA shunt, among them glutamate, the precursor
of GABA synthesis, and intermediates of TCA cycle, have not shown
significant changes (Hogema et al. 2001; Gibson et al. 2002).
The high accumulation of GHB raises questions on the efficiency of its
catabolism. The oxidation of GHB to SSA is a rate-limiting step, proceeding
at approximately 1,000th of the rate at which SSA is oxidized to succinate by
SSADH (Kaufman and Nelson 1991). In mammals two enzymes are thought
to be responsible for the catabolism of GHB to SSA: (1) Schaller et al. (1999)
suggest a role for SSA reductase/AFAR (also referred to as GHBDH) in
the reversible conversion of SSA to GHB; (2) Kaufman and Nelson (1991)
have shown that aldehyde reductase (glucuronate reductase or l-hexonate
dehydrogenase, EC 1.1.1.19, in their nomenclature) can oxidize GHB in
unison with the reduction of glucuronate.