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Proteomic Study Finds Obstetric, Pediatric Medications May Cause Long-Term Damage

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Certain types of drugs that are commonly used in obstetric and pediatric medicines may have long-term damaging effects, researchers who performed a large proteomic study found.
 
In the study, described in the December issue of Molecular & Cellular Proteomics, the researchers said that sedatives, anesthetics, and anticonvulsants, such as ketamine, nitrous oxide, propofol, diazepam, phenobarbital, and others are used “frequently” in obstetric and pediatric medications. Previous studies have associated exposure to such medications with neurological abnormalities, with long-term effects including mid-behavioral changes such as hyperactivity and learning disabilities as well as more serious maladies such as severe mental retardation and organ malformations.
 
The authors of the MCP paper, however, said that their work is the first “systematic report on acute, subacute, and long-term proteome changes of the developing cerebral cortex in infant rodents” exposed to N-methyl-D-aspartate receptor blockage with dizocilpine, or gamma-aminobutyric acid subtype A receptor activation with phenobarbital.
 
In their research, the authors sought to explore the long-term and acute changes in the brain proteome “following NMDAR antagonist or GABAAR exposure in infancy” to gain an understanding of development changes that may occur, and to identify proteins that may be involved in the pathomechanism of “observed neurological deficits or in reparative processes.”
 
The results of their research, they wrote, “point toward a number of phenomena whose dysregulation can influence normal development, give rise to neurologic and neurocognitive deficits, and thus contribute to unfavorable outcomes of infants exposed to drugs or toxins that decrease neuronal excitation.”
 
The research team studied six-day old mice that had been treated with doses of either the NMDA receptor blocker dizocilpine or the GABA subtype A receptor activator phenobarbital. The brains of the mice were then analyzed at different time points for changes in protein levels.
 
The rodent brain, the authors wrote, is especially sensitive to otherwise harmless influences during the first three weeks of its life because during this time brain growth is at its peak. During this time, extensive synaptogenesis, glial proliferation, myelination, and reorganization events occur.
 
Comparing the brains of the infant mice who had been given the drugs to the brains of infant mice who had been unmedicated, the authors detected noticeable differences: In 2-DE protein patterns they saw “reproducible qualitative and quantitative differences” in 28, 14, and 18 protein spots of infant mice treated with dizocilpine compared to untreated littermates at one week, two weeks, and four weeks after treatment, the researchers said in their study.
 
In mice treated with phenobarbital compared to those who weren’t, the researchers saw differences in 24, 19, and four proteins spots at one week, two weeks, and four weeks after treatment.
 

“This emphasizes that a short-term modulation of NMDAR or GABAAR transmission in infancy can lead to long lasting effects.”

Mass spectrometry resulted in similar differential detections. In dizocilpine-treated mice 25, 12, and 16 discrete proteins were identified at one week, two weeks, and four weeks, and in phenobarbital-treated mice, 19, 18, and four discrete proteins were identified at one week, two weeks, and four weeks.
 
Several proteins were found to be differentially expressed in both dizocilpine- and phenobarbital-treated mice, including glyoxalase 1, peroxiredoxin, and cell division cycle 10 homolog, though in several cases differences in regulation of the proteins were observed “with regard to timing, isoprotein, and quality/quantity of regulation depending on the drug applied,” the authors wrote.
 
The altered proteins found in the drug-treated mice were associated with apoptosis, oxidative stress, inflammation, cell maintenance and growth, synaptic function/vesicular transport, and neuronal circuit formation.
 
Among the proteins that were altered in mice that were treated with dizocilpine or phenobarbital were DJ1 and peroxiredoxin 1, associated with oxidative stress and apoptosis; glial fibrillary acidic protein, which have roles in growth and energy metabolism; and collapsin response mediator protein, involved in neuronal migration, axon growth, and guidance.
 
The changes observed in the infant mice, the researchers added, do not appear in older mice whose brains are no longer developing, suggesting that the alterations in the proteome thus appear to be age-dependent.
 
In their paper, they said that it is particularly notable that the drug-induced proteome changes occur even four weeks after treatment when the mice have almost reached adulthood.
 
“This emphasizes that a short-term modulation of NMDAR or GABAAR transmission in infancy can lead to long-lasting effects,” they said. Sustained or “newly evolved” differences in brain protein phenotypes four weeks after drug exposure may be secondary changes such as morphological alterations, the researchers said.
 
“In comparison with the adult brain, suppression of neuronal activity disturbs vulnerable and developing systems in which the cellular phenotypes, protein concentrations, protein compositions, and interactions change rapidly according to a predetermined developmental program,” they said.
 
While little is known about the effects of sedative and antiepileptic drugs on the developing brain, their study, a comparative analysis of the brain proteome, can elucidate “the nature of the developmental events that may be disrupted by drug-induced changes in neuronal activity and possibly also by other developmental insults,” they added.
 
Their findings, they said, “are highly relevant from a clinical perspective” because compounds that act as NMDAR antagonists or GABAAR agonists are commonly used in obstetric/pediatric medicines as sedatives, tranquilizers, anticonvulsants, or anesthetics. Such drugs also have high abuse potential, they said.
 
“The developing human brain may therefore be exposed to these agents,” they said.

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