Related Experiment Videos
Toxicity of fructose-1,6-bisphosphate in developing normoxic rats
Z Vexler1, M Berrios, P C Ursell
1Department of Paediatrics (Neonatology), University of California, San Francisco, USA.
Insights
Fructose-1,6-bisphosphate shows promise for neonatal CNS injury. Toxicity studies in rats indicate a safe dose of 4,000 mg/kg, suggesting potential for safe use in human neonates.
Area of Science:
- Biochemistry
- Neonatal Medicine
- Toxicology
Background:
- Hypoxic/ischemic central nervous system (CNS) injury is a significant concern in neonates.
- Fructose-1,6-bisphosphate has demonstrated neuroprotective effects in preclinical models of CNS injury.
Purpose of the Study:
- To determine the toxicity and safety profile of fructose-1,6-bisphosphate in neonatal rats before potential human trials.
- To establish a safe dosage range for fructose-1,6-bisphosphate administration in neonatal subjects.
Main Methods:
- Neonatal rats (7 days old) received intraperitoneal injections of saline or varying doses of fructose-1,6-bisphosphate (4,000, 6,000, or 8,000 mg/kg).
- Blood parameters (calcium, phosphate, BUN, creatinine), liver enzymes, and organ pathology were assessed at multiple time points.
- Animal survival, growth rates, and weight were monitored throughout the study period.
Main Results:
- A dose of 4,000 mg/kg of fructose-1,6-bisphosphate was well-tolerated, with no observed toxicity or injury in neonatal rats.
- Higher doses (6,000 and 8,000 mg/kg) resulted in significant mortality and some instances of pulmonary hemorrhage.
- Transient decreases in calcium and increases in phosphate were observed at higher doses, similar to sodium phosphate administration.
Conclusions:
- Fructose-1,6-bisphosphate exhibits a wide safety margin in neonatal rats, with 4,000 mg/kg being a safe dose.
- The observed biochemical changes were transient and comparable to sodium phosphate administration.
- These findings support the potential safety of fructose-1,6-bisphosphate for treating neonatal CNS injury.
Abstract:
Giving 500 mg/kg of fructose-1,6-bisphosphate intraperitoneally decreases hypoxic/ischaemic CNS injury of neonatal rats. Before administering fructose-1,6-bisphosphate to human neonates, its toxicity must be determined in neonatal animals. Thus, saline or 4,000, 6,000, or 8,000 mg/kg of fructose-1,6-bisphosphate was given intraperitoneally to normoxic 7 days old rats. One, 2, and 24 hr and 7 days later, blood Ca2+, PO(4)3-, blood urea nitrogen, and creatinine concentrations, and aspartate aminotransferase activity were measured. Organ pathology was determined at necropsy. Pups receiving 4,000 mg/kg of fructose-1,6-bisphosphate survived without evidence of injury or toxicity. All animals receiving 8,000 mg/kg and 27 percent of those receiving 6,000 mg/kg of fructose-1,6-bisphosphate died. Surviving fructose-1,6-bisphosphate-treated animals grew at the same rates and had similar weights as saline-treated animals. Nineteen percent of pups given 6,000 or 8,000 mg/kg of fructose-1,6-bisphosphate had mild perivascular fluid cuffing and/or microscopic pulmonary haemorrhage, but none of the animals given 4,000 mg/kg of the compound had evidence of injury. No other organ pathology was found in any of the animals. Renal and hepatic function were normal in all animals. Fructose-1,6-bisphosphate administration was associated with a significant increase in the fructose-1,6-bisphosphate concentration of blood. Administering 4,000 to 8,000 mg/kg of fructose-1,6-bisphosphate significantly decreased Ca2+ concentrations and increased PO(4)3- concentrations 1 and 2 hrs after fructose-1,6-bisphosphate administration. Similar changes in Ca2+ and PO(4)3- concentrations occurred after the administration of 10 mmol/kg of sodium phosphate. The wide margin of safety for fructose-1,6-bisphosphate (8 times the dose needed to prevent or reduce CNS injury) may render fructose-1,6-bisphosphate safe for use in neonates.