Scientists have identified a key biochemical mechanism in the formation of new synapses in the brain that can be disrupted by the antiepileptic medication gabapentin, according to a recent study. The findings shed light on the pathophysiology of certain neurological diseases and raise concerns about the long-term effects of gabapentin on the developing brain.

In the study published in the journal Cell online on October 8, Cagla Eroglu, Ph.D., and colleagues found that the formation of new excitatory synapses in the central nervous system is mediated by the interaction between thrombospondin—a type of protein secreted by astrocytes with a variety of functions—and the cell-surface receptor known as alpha2delta-1. In both in-vitro and mouse models, neurons that had been engineered to overexpress the alpha2delta-1 receptor generated more excitatory synapses upon exposure to thrombospondin than wild-type neurons.

The findings also describe an important part of gabapentin's therapeutic effects on epilepsy and neuropathic pain and point to crucial biochemical processes involved in these conditions. As an antagonist of the alpha2delta-1 receptor, gabapentin interferes with the binding of thrombospondin and thus inhibits the formation of excitatory synapses.

Pregabalin, a medication used to treat fibromyalgia, has a similar mechanism of action to that of gabapentin. “We have not directly studied pregabalin, but we assume it works the same way,” Ben Barres, M.D., Ph.D., told Psychiatric News.

Barres is a professor and chair of neurobiology at Stanford University and senior author of the study. He explained that alpha2delta-1 receptor antagonism may not be the only component contributing to gabapentin's therapeutic effect, because alpha2delta-1 activation has also been linked to upregulation of calcium channels in the cell surface. Epilepsy, neuropathic pain, and possibly other neurological disorders may be related to both the increased number of excitatory synapses and elevated levels of synaptic calcium channels.

Meanwhile, these findings raise concerns that gabapentin, by inhibiting the formation of new synapses, may affect normal brain development in children if they are exposed to the drug in utero or during early life, which are periods of rapid neuronal and synaptic growth.

Gabapentin is approved by the Food and Drug Administration as an adjunctive treatment for partial seizures in pediatric patients as young as age 3. Both gabapentin and pregabalin have a pregnancy classification C designation because of fetotoxic effects in animal studies. Gabapentin is secreted into human milk, while the secretion of pregabalin in milk has not been studied.

Because of the theoretical risk in blocking synaptic formations, Barres and colleagues expressed concerns about the long-term developmental outcomes in children with early exposure to gabapentin. “There is a long, rich history of serious side effects in fetuses exposed to epilepsy treatments,” Barres noted. “Gabapentin may well be safe, and many pregnant women have taken gabapentin without obvious bad effects. However, there may be some subtle or long-term effects.” The effects, he suspects, may be reflected in cognitive function and development as the young brain matures.

A study published in the April 16 New England Journal of Medicine warned of long-term detrimental effects of valproate, another antiepileptic drug, on the cognitive development of children who were exposed to the drug in utero as measured by their IQ scores at age 3 (Psychiatric News, May 15). That study prospectively followed and compared women with epilepsy who were treated with four commonly prescribed antiepileptics. However, gabapentin was not included in the comparison, nor were the children compared with those who had no exposure to any antiepileptic drugs.

Despite the developmental concerns, uncontrolled epilepsy in pregnant women certainly poses serious risks to the mother and fetus. Nevertheless, more long-term research is needed to clarify the true consequences of using each antiepileptic drug.

The current study on thrombospondin and alpha2delta-1 receptor was funded by grants from the National Institute on Drug Abuse (NIDA), National Heart, Lung and Blood Institute, National Institute of Neurological Disorders and Stroke, and National Institute of Dental and Craniofacial Research.

NIDA has a particular interest in this research because of its implications for studying the neuropathology of addiction, Barres said. Many studies suggest that astrocytes and thrombospondin play an important role in addiction and that the powerful, long-lasting cravings that remain even after a period of abstinence, may be the result of new synaptic formation in the brain caused by the substance of abuse. Understanding this process may reveal strategies for addiction treatment and relapse prevention, he suggested. Currently, gabapentin is being studied in clinical trials as a treatment for drug addiction and withdrawal symptoms.

“Gabapentin Receptor 2-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis” is posted at <www.cell.com/fulltext/S0092-8674(09)01185-4>.