Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.

Natale, G., Calabrese, V., Marino, G., Campanelli, F., Urciuolo, F., De Iure, A., Ghiglieri, V., Calabresi, P., Bossola, M., Picconi, B., Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease, <<CELL DEATH DISCOVERY>>, 2021; 7 (1): 295-N/A. [doi:10.1038/s41420-021-00685-9] [http://hdl.handle.net/10807/202630]

Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease

Campanelli, F.;Urciuolo, F.;Calabresi, P.;Bossola, M.;
2021

Abstract

Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.
Inglese
Natale, G., Calabrese, V., Marino, G., Campanelli, F., Urciuolo, F., De Iure, A., Ghiglieri, V., Calabresi, P., Bossola, M., Picconi, B., Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease, <<CELL DEATH DISCOVERY>>, 2021; 7 (1): 295-N/A. [doi:10.1038/s41420-021-00685-9] [http://hdl.handle.net/10807/202630]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/202630
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