Propylene glycol produces excessive apoptosis in the developing mouse brain, alone and in combination with phenobarbital

Abstract

Propylene Glycol (PG) is a common solvent used in medical preparations. It is “generally recognized as safe” at regulated concentrations, however its apoptotic potential is unknown. C57BL/6 mice (P4–30) were exposed to PG to examine whether PG could produce apoptosis in the developing CNS. PG triggered widespread apoptotic neurodegeneration with the greatest damage at P7. Significant apoptosis was observed at doses as low as 2mL/kg. These findings have implications for the safety of drug preparations used in pediatric medicine. The anticonvulsant phenobarbital (PB), which alone produces apoptosis in the immature CNS, is prepared in 68% PG and 10% Ethanol (EtOH). We assessed whether PG contributes to the neurotoxic potential of PB. The agents (both at sub-toxic doses) produce significantly more apoptosis when used in combination. In conclusion, finding an alternative non-apoptotic solvent that can be used as a substitute for PG may be beneficial to patients.

Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis

“…Since many solvents are neurotoxic in developing brain (Farber et al, 2010; Hanslick et al, 2009; Lau et al, 2012), vismodegib (LC Laboratories, Woburn, MA, USA), cyclopamine (LC Laboratories, Woburn, MA, USA), jervine (Santa Cruz Biotechnology, Dallas, TX, USA), mifepristone (Sigma-Aldrich, St. Louis, MO, USA), itraconazole (Santa Cruz Biotechnology, Dallas, TX, USA), and fluocinolone acetonide (Sigma-Aldrich, St. Louis, MO, USA) were dissolved in palm oil and injected intraperitoneally. Injections of cytosine arabinoside (AraC; Sigma-Aldrich, St. Louis, MO, USA) and dexamethasone sodium phosphate (Voigt Global Distribution LLC, Lawrence, KS, USA) were dissolved in saline.…”

The propylene glycol research project to illustrate the feasibility and difficulties to study toxicokinetics in neonates

“…Differences in permeability of the blood-brain barrier, differences in sensitivity to osmolar shifts or synergistic pharmacodynamic effects (e.g. propylene glycol + phenobarbital, Lau et al, 2012) may result in population specific pharmacodynamics…”

“…In addition to the absence of PK estimates, we also have to consider potential age-related, PD differences (e.g. effects on the developing central nervous system compared to the mature, adult brain) (Lau et al, 2012).…”

Evidence from a mouse model on the dangers of thirdhand electronic cigarette exposure during early life

“…Although formaldehyde, acetaldehyde, benzene, phenol and benzaldehyde were detected in the e-vapour, only nicotine and propylene glycol were detected in the towel. Interestingly, propylene glycol has been shown to be detrimental to the developing brain [13]. However, another method is still needed in future studies to identify other toxic chemical(s) responsible for the suppression of organ development.…”