Changes in nucleotide and nucleoside metabolism in zebrafish brain exposed to paraquat and 6-hydroxydopamine

Degeneration of dopaminergic neurons is associated with several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and Huntington's disease. To find new therapies for these conditions, animal models based on exposure to toxins, such as paraquat (Pq) or 6-hydroxydopamine (6-OHDA), have been developed. Purinergic signaling has emerged as a key factor in motor illness. This study evaluated the influence of Pq and 6-OHDA on ATP metabolism and gene expression of nucleotide- and nucleoside-metabolizing enzymes in zebrafish brain. Adult zebrafish were injected i.p. with saline or Pq (10 or 20 mg/kg) at two-day intervals for a total of six doses. For 6-OHDA treatment, zebrafish received one i.p. injection of saline or 6-OHDA (25 or 50 mg/kg). Six days after the 6-OHDA treatment or 6 i.p injections of Pq, ATP metabolism and gene expression assays were evaluated in zebrafish brain. A decrease in extracellular adenosine (ADO) catabolism was observed in Pq-treated animals compared to the controls. In 6-OHDA-treated fish, there were no changes in ATP levels; however, ADP levels were altered and AMP levels decreased at both doses tested. Meanwhile, ADO levels increased compared to the control. Both treatments led to increased extracellular inosine (INO) levels. Changes in adenosine deaminase gene expression were observed following 6-OHDA exposure. Given the observed alterations in ATP and adenosine catabolism, purinergic signaling emerges as a regulatory mechanism that could be targeted in the development of therapeutic strategies aimed at mitigating neurotoxic damage and preserving neuronal function.