Abstract
Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.
Highlights
Introduction published maps and institutional affilAcute liver failure (ALF) is characterized by rapid loss of liver function, which may result in a neurologically specific syndrome defined as hepatic encephalopathy (HE), encompassing symptoms related to systemic and central disturbances [1,2]
We address the question of whether a selectively reduced circulating active form of TGF-β1 in mice injected with anti-TGF-β1 affects the expression and distribution of pre- and post-synaptic proteins and electrophysiological parameters, thereby contributing to glutamatergic neurotransmission impairment observed in the ALF mice
We analyzed the effect of TGF-β1 reduced signaling on the expression of synaptic
Summary
Acute liver failure (ALF) is characterized by rapid loss of liver function, which may result in a neurologically specific syndrome defined as hepatic encephalopathy (HE), encompassing symptoms related to systemic and central disturbances [1,2]. Thrombocytopenia is clinically the most frequent and common complication observed in patients with ALF. It is assumed that a decrease in platelet count can define the severity of liver dysfunction. Decreasing platelet amount signals systemic complications, contributing to HE-related alterations, and the need for a liver transplant. In the context of our study, platelets are the main source of transforming growth factor (TGF-β1), a cytokine exerting regulatory and homeostatic functions [3,4]. The bioavailability of TGF-βs is regulated by its release from cells, and by extracellular mechanisms.
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