Serotonin involvement in okadaic acid-induced diarrhoea in vivo

Abstract

The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms including nausea, vomiting and diarrhoea. These phycotoxins are Ser/Thr phosphatase inhibitors, which produce hyperphosphorylation in cellular proteins. However, this inhibition does not fully explain the symptomatology reported and other targets could be relevant to the toxicity. Previous studies have indicated a feasible involvement of the nervous system. We performed a set of in vivo approaches to elucidate whether neuropeptide Y (NPY), Peptide YY (PYY) or serotonin (5-HT) was implicated in the early OA-induced diarrhoea. Fasted Swiss female mice were administered NPY, PYY(3–36) or cyproheptadine intraperitoneal prior to oral OA treatment (250 µg/kg). A non-significant delay in diarrhoea onset was observed for NPY (107 µg/kg) and PYY(3–36) (1 mg/kg) pre-treatment. On the contrary, the serotonin antagonist cyproheptadine was able to block (10 mg/kg) or delay (0.1 and 1 mg/kg) diarrhoea onset suggesting a role of 5-HT. This is the first report of the possible involvement of serotonin in OA-induced poisoning.

Current Trends and New Challenges in Marine Phycotoxins

“…Results from in vitro studies had suggested that the potent pro-absorptive peptide neuropeptide Y (NPY) was altered after OA treatment in a neuroblastoma cell line [ 177 ]. However, NPY administration prior to OA did not modify OA-induced poisoning in mice, but in the same study, serotonin was directly involved in OA-induced diarrhea [ 178 ]. The secretory role of serotonin in the pathophysiology of diarrhea has been largely reported [ 176 , 179 ].…”

“…OMIC techniques may be a valuable tool in understanding OA-altered pathways [ 184 ]. After ingestion of DSTs-bearing bivalves, toxins are localized mainly at the gastrointestinal tissues [ 178 ]. They cause diarrhea stimulating Na + secretion by intestinal cells, leading to intraluminal gastrointestinal (GI) fluid accumulation and abdominal cramping [ 14 ].…”

“…These alterations have been traditionally related to OA inhibition of PPs activity [ 189 , 190 ]. However, the broad symptomatology of DSP cannot be attributed only to inhibition of PPs [ 72 , 178 , 180 ]. Due to intestine complex structure and tight regulated physiology, understanding the interplay between different components (e.g., enterocytes and the enteric nervous system) in OA response might shed some light to OA mode of action.…”

Okadaic Acid Is at Least as Toxic as Dinophysistoxin-1 after Repeated Administration to Mice by Gavage

“…For example, PP inhibition by OA can both increase and reduce intestinal paracellular permeability [14,15], and increased paracellular permeability can cause fluid accumulation and diarrhea. Moreover, non-PP mechanisms involving neuropeptide Y and serotonin may also be mechanistically responsible for OA-induced diarrhea [16,17]. However, the mechanisms responsible for the toxicities of these compounds are poorly understood [13].…”

Acute Toxicity by Oral Co-Exposure to Palytoxin and Okadaic Acid in Mice

“…In particular, diarrhea as an acute effect of OA is ascribed mainly to an increased phosphorylation level of proteins involved in ions secretion and of cytoskeletal/junctional elements of intestinal cells controlling paracellular permeability to solutes. This effect is assumed to cause a passive loss of fluids from the intestinal wall into the lumen, leading to diarrhea [8,[16][17][18][19], but other mechanisms have been also suggested [18,20].…”