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  • Title: Bacterial endotoxin inhibits LHRH secretion following the increased release of hypothalamic GABA levels. Different effects on amino acid neurotransmitter release.
    Author: Feleder C, Refojo D, Jarry H, Wuttke W, Moguilevsky JA.
    Journal: Neuroimmunomodulation; 1996; 3(6):342-51. PubMed ID: 9266545.
    Abstract:
    Immune system disorders are often accompanied by alterations in the reproductive axis. The bacterial endotoxin (lipopolysaccharide, LPS) has inflammatory effects and activates cytokine release in the pituitary and hypothalamus. LPS inhibition of luteinizing-hormone-releasing hormone (LHRH) release at the hypothalamic level appears to be associated with modifications in the inhibitory GABAergic neurotransmitter system. Then, knowing that gamma-aminobutyric acid (GABA) mediates other neurotransmitter effects in the central nervous system, the possibility arises that this amino acid might mediate the effect of LPS on LHRH release by modifying amino acid neurotransmitter release at the hypothalamic level. Therefore, the present study was designed to investigate a possible mediatory function of the GABAergic system in the LPS-induced inhibition of LHRH secretion. To this end, the modifications in the excitatory (glutamate, Glu) and inhibitory (taurine, Tau, and GABA) amino acid neurotransmitter release after the application of GABA-A and GABA-B antagonists, respectively, were studied and the effects of LPS on their release determined. Male rats were decapitated at 9.00 h, and the preoptic/mediobasal hypothalamic area (POA/MBH) was dissected and superfused with Earle's balanced salt solution. Superfusate fractions were collected at 15-min intervals after a 60-min stabilization superfusion period. LPS (100 ng/ml) was then added to the superfusion medium over 1 h in three different experimental designs: (1) LPS only (2) LPS simultaneously with bicuculline (GABA-A antagonist) or with phaclofen (GABA-B antagonist), and (3) LPS and subsequently bicuculline or phaclofen, performed in different experiments. This was followed by a wash-out period. The POA/MBH fragments were then subjected to a 56-mM K+ stimulus. Control POA/MBH fragments were continuously superfused with Earle's solution. As expected, LHRH release was significantly reduced (p < 0.05) during and following exposure to LPS. At the same time, GABA and Tau concentrations increased in the superfusion medium, while Glu decreased significantly compared with the control group. The GABA antagonists blocked and reversed the LPS effect on LHRH secretion. No significant differences were found between the effect of GABA-A and-B receptor antagonists. Meanwhile, GABA levels measured in the control group did not increase since they were the same as when LPS was added alone. Furthermore, LPS was without effect on Glu and Tau release in the presence of the GABA blockers. Therefore, the effect of the bacterial endotoxin was blocked. These observations indicate that there is an increase in GABA release that becomes significant at the same time when LHRH release is decreased. This effect can be blocked by GABA-specific receptor blockers. The effect of LPS is thus exerted by increasing GABA. The elevated GABA levels may also reduce Glu release and enhance Tau release. These modifications in neurotransmitter release may also contribute to LHRH suppression. These effects may be explained by the stimulation of cytokines of neuronal and/or glial origin that interact with the excitatory and inhibitory amino acids.
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