Sulfamethoxazole induces zinc changes at hippocampal mossy fiber synapses from pregnant rats

Abstract

The accumulation of intracellular ionic zinc and pharmaceutical compounds, like the antibiotic sulfamethoxazole, may contribute to various neuropathologies. Sulfamethoxazole and the drug trimethoprim, are inhibitors of enzymes involved in the synthesis of tetrahydrofolate and also of carbonic anhydrases. The inhibition of the latter enzymes, which are localized both intra- and extracellularly and have a key role in pH regulation, causes alkalinization that is associated with higher spontaneous transmitter release. Intense synaptic stimulation causes the entry of released zinc into postsynaptic neurons, through glutamate receptor channels or voltage dependent calcium channels. The aim of this study was to evaluate the effect of sulfamethoxazole (180 μM) on basal postsynaptic zinc and to compare it with that caused by two depolarizing media, containing high potassium or tetraethylammonium, which may induce long term synaptic plasticity. The studies were performed in brain slices from gestating rats, at the mossy fiber synapses from hippocampal CA3 area, using the zinc indicator Newport Green. In the presence of KCl (20 mM) and sulfamethoxazole (180 μM) the zinc signals were enhanced, unlike in tetraethylammonium (25 mM). After sulfamethoxazole the tetraethylammonium evoked zinc signal had reduced amplitude. Thus, the data suggests that sulfamethoxazole enhances transmitter release affecting synaptic zinc physiology.

Trimethoprim-sulfamethoxazole-induced hyponatremia in an elderly lady with Achromobacter xylosoxidans pneumonia

“…SIADH and enhanced natriuresis represent parsimonious and plausible mechanisms explaining the observed set of effects, though a coherent model physio-mechanistically detailing the development of hyponatremia in the setting of TMP/SMX monotherapy remains to be more thoroughly elucidated. We discuss and detail the following effects extensively since sulfamethoxazole may plausibly enhance the hypothalamic release of vasopressin, [ 37 ] which may powerfully and multi-mechanistically modulate total body water and sodium homeostasis (Table 4 ). [ 38 ] Serum osmolarity, volume, and serum renin regulate the release of the pleiotropically-active nonapeptide vasopressin, which exerts a panoply of neural, neurohumoral, and renal effects from neurons of the paraventricular and supraoptic nuclei.…”

“…Sulfamethoxazole inhibits intra-neuraxial [ 37 ] and proximal convoluted tubule carbonic anhydrase. [ 37 ] The latter effect reduces the enzymatic generation of bicarbonate ions luminally available to bind sodium ions, blunting the reabsorption of sodium ions and nephric capacity to augment effective arterial blood volume.…”

“…Sulfamethoxazole inhibits intra-neuraxial [ 37 ] and proximal convoluted tubule carbonic anhydrase. [ 37 ] The latter effect reduces the enzymatic generation of bicarbonate ions luminally available to bind sodium ions, blunting the reabsorption of sodium ions and nephric capacity to augment effective arterial blood volume. [ 49 ] The former effect promotes acidification of the neural interstitial milieu, enhancing the presynaptic and axon terminal vesicular uptake of the divalent cation zinc, co-released with glutamate.…”

“…[ 50 ] Sulfamethoxazole-mediated neural interstitial acidification and enhanced release of glutamate may enhance the release of vasopressin by the hypothalamus. [ 37 ] Zinc may putatively substitute the divalent cation magnesium and antagonize synaptic and extra-synaptic NMDA glutamate receptors and attenuate sulfamethoxazole-mediated potentiation of glutamate receptor modulated signaling. [ 50 ] We suggest at traditionally utilized doses, enhanced co-release of zinc sufficiently buffers the co-release of glutamate and mitigates putative sulfamethoxazole-induced amplification of vasopressin release.…”

“…[ 4 , 9 , 17 , 30 , 33 ] We suggest pathways sharing mechanistic nodes in common with the foregoingly described set of effects may represent chief intermediary mechanisms generating drug-induced SIADH. [ 36 , 37 , 40 ] We present these considerations conjecturally and subject them to the experimental interrogative efforts of Eminent internists, nephrologists, intensivists, and neurophysiologists.…”