Prevention of Latently Expressed CYP2C11, CYP3A2, and Growth Hormone Defects in Neonatally Monosodium Glutamate-Treated Male Rats by theN-Methyl-d-Aspartate Receptor Antagonist Dizocilpine Maleate

Abstract

Neonatal administration of monosodium glutamate (MSG) can produce latently expressed defects in drug metabolism and growth hormone secretion as well as stunted growth and obesity. Instead of secreting growth hormone in the masculine episodic profile, plasma hormone levels are generally undetectable in affected adult male rats. Moreover, male-specific isoforms of cytochrome P450 (P450; e.g., CYP2C11 and CYP3A2), whose combined levels comprise the bulk of the total hepatic P450 in adult male rats, are similarly undetectable in these animals. Since "signaling elements" in the masculine episodic growth hormone profile are solely responsible for the elevated characteristic malelike expression levels of CYP2C11 and CYP3A2, suppression of the isoforms in the MSG-treated rats appeared to be caused by the simple absence of the hormone from the circulation. However, the reported failures of restored physiologic masculine growth hormone profiles to correct the P450 defects suggested the occurrence of direct MSG-induced liver damage independent of the well known hypothalamic lesions produced by the amino acid. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent noncompetitive N-methyl-D-aspartate receptor antagonist of glutamate, completely prevented the adverse effects of neonatal MSG treatment on P450 expression, growth hormone secretion, and growth parameters, indicating that the amino acid-induced defects are solely a result of neuronal (i.e., hypothalamic) damage produced at the time of MSG exposure. The irreversibility of the P450 damage is described as resulting from secondary defects initially induced by the neuronal lesions.

Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity

“…After repeated high doses of MSG, mice become obese in adulthood, as attested by increased Lee index and adipocyte hypertrophy (Fabres-Machado and Saito, 1995;Dolnikoff et al, 2001). These animals also present several neuroendocrine dysfunctions as decreased growth hormone secretion and hyperinsulinaemia (Nemeroff et al, 1978;Scallet and Olney, 1986;Maiter et al, 1991;Fabres-Machado and Saito, 1995;Kaufhold et al, 2002), without hyperphagia (Bunyan et al, 1976). On the other hand animals with electrolytic lesion in the ventromedial hypothalamus (VMH) are obese being hyperphagic (Baile et al, 1970;Bray et al, 1981) but obesity can occur even without increase in food intake (Han and Frohman, 1970).…”

Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite

“…The authors showed increases in GLU levels and activation of GLU-receptors after neonatal s.c. administration of MSG at doses of 4 mg/g body weight and an increase in glial cell reactivity and important changes in NMDA-R molecular composition, with signs of neuronal damage. Kaufhold et al (2002) were able to prevent the adverse effects of neonatal MSG treatment by concurrent administration of a selective and highly potent noncompetitive NMDA-R antagonist of GLU.…”

Insulin-regulated aminopeptidase in adipocyte is Cys-specific and affected by obesity

“…On the 22nd day, the animals were weaned and the female was removed from the cage. On the 90th day, obesity was evaluated by Lee index, calculated by body mass (g) 0.33 /naso-anal length (cm) (Nakagawa et al 2000, Kaufhold et al 2002. Thus, obese (MSG) animals were selected from i-MSG group by Lee index O0.300 and the i-control rats were subdivided into two groups: control (Lee index %0.300) and FD control (control animals fasted for 72 h).…”