Fingolimod’s effects include neuronal production of BDNF
Side effects can sideline even the most successful drug. For fingolimod (Gilenya), the first oral therapy for MS, “off-target effects” are piling up: The agent influences brain cells in addition to the immune cells that underlie its well-documented modus operandi. But thus far, many of these consequences appear beneficial and might even contribute to the drug’s power over MS. New research from neuroscientist Yves-Alain Barde of the University of Basel in Switzerland shows that fingolimod increases production of brain-derived neurotrophic factor (BDNF), a potent survival molecule—and that the medication counteracts neuronal death (Deogracias et al., 2012). The work suggests that the agent nurtures neurons directly in addition to preventing immune cells from attacking them.
The work is strong, says Lawrence Steinman, a neuroimmunologist at Stanford University: “I’m really bullish about it.” The new discoveries might also help explain the observation that the drug preserves brain volume in patients and experimental animals, Steinman adds. These effects suggested that the medication could aid MS patients with primary-progressive MS, who don’t respond to immunosuppressive treatments, and Novartis, which markets fingolimod, is currently running a clinical trial of the drug in those individuals.
One might assume that an MS therapy would work in the brain, but most of them—including fingolimod—perturb immune cells outside the central nervous system (CNS). The compound’s well-established mechanism is to bind to the sphingosine 1-phosphate 1 (S1P1) receptor on lymphocytes and prevent them from leaving lymph nodes and entering the bloodstream. In addition, however, fingolimod gets into the brain. Barde wondered whether the medication directly affects neurons and whether BDNF might execute fingolimod’s power to protect against brain-tissue loss.
To probe those questions, the researchers tested fingolimod’s impact on BDNF levels in mouse neurons grown in a dish. Measurements of protein as well as mRNA quantities showed that the drug did increase BDNF production. Then they investigated the agent’s effects in vivo. In normal mice injected with the drug, the cortex, hippocampus, and striatum made increased amounts of BDNF. In a mouse model of the neurodevelopmental disorder Rett syndrome, in which BDNF production is significantly compromised, fingolimod restored brain BDNF quantities and improved classic motor symptoms during 4 weeks of drug injection. Treatment also prevented the brain loss observed in untreated mice, as measured by weighing the striatum after sacrificing the animals. In the clinic, MRI studies indicate that fingolimod preserves brain volume better than other MS drugs do—an observation whose mechanism is unknown—and the new results suggest that this effect could arise from BDNF’s capacity to sustain neurons, says Jerold Chun, a neuroimmunologist at the Scripps Research Institute in San Diego, California.
Whether a rise in brain BDNF quantities could protect against MS remains unclear, but because MS features neuronal damage and axon loss, “having a growth factor around at high levels may be beneficial,” Barde says. Although it’s not news that fingolimod crosses the blood-brain barrier—an unusual feature for an MS drug—the study reveals a potential benefit of that talent. “People have been struggling for years to increase [BDNF] levels in the brain,” Barde says. “Here comes a drug that gets into the brain and increases BDNF in addition to its other effects.”
Other drugs for MS also increase BDNF quantities, but in a different way. Glatiramer acetate and laquinimod enlist T helper cells outside the brain to enter the CNS, where they contribute to immunosuppression and release BDNF, thus inflating its concentration at inflammatory lesions and in the bloodstream. Adding further to possible connections between BDNF and MS, preliminary work hints that patients carry unusually small amounts of the compound in their bloodstream (Tongiorgi et al., 2012). At first glance, this observation might suggest that MS patients suffer from a lack of BDNF and would benefit from a boost, but the situation is more complicated than that. Other evidence suggests that BDNF can bolster the survival of autoreactive T cells, which would potentially exacerbate MS.
Fingolimod’s ability to bump up BDNF quantities joins a growing list of the drug’s effects in the brain. Last year, Chun and colleagues reported that astrocytes mediate the benefits they saw from fingolimod in the experimental autoimmune encephalomyelitis model of MS (Choi et al., 2011). Barde emphasizes that his new findings don’t challenge the view that other cell types—including astrocytes, oligodendrocytes, and microglia—could also deliver drug actions. The benefits derived from these cells could stem from a number of as-yet-undescribed primary or downstream actions, Chun says, given the growing number of roles these cells play in neuronal support, communication, and protection.
For Novartis, the new results “are certainly of interest … and could indicate direct protective effects of Gilenya on neurons in the CNS,” writes neuroscientist Volker Brinkmann of Novartis in Basel, Switzerland, in an email. But, he adds, it is “difficult to judge” how much of the drug’s benefits arise from its activities in the CNS as opposed to its effects on immune cells.
Exactly how fingolimod entices neurons to make more BDNF remains unclear, but Barde’s work shows—at least in a dish of cultured cortical neurons—that it does, and that this drug-induced BDNF protects the cells from death spurred by a toxic treatment that normally kills them. Fingolimod sets in motion a well-established signaling pathway that starts with increased neuronal excitability and culminates in production of the support factor. Along the way, other biochemical and genetic events occur—such as activation of the cyclic-AMP response element-binding protein, or CREB, pathway—in what he describes as “a classical means of increasing BDNF.” Nevertheless, Barde says, “there are of course many unknowns,” such as what exactly leads to the drug-induced upsurge in neuronal excitability. A better understanding of the S1P1 receptor’s activities in neurons and other brain cells might help explain all the ways fingolimod curbs MS. Such information could reveal additional ways in which “off-target” effects turn out to be very much on target.
Key open questions
- How do BDNF expression patterns change in the brains of MS patients as disease progresses?
- What precise events take place at neuronal S1P1 receptors after fingolimod binds, and how do they lead to BDNF production?
- Will fingolimod be useful in primary-progressive MS?
- Fingolimod did not increase BDNF production globally in the brain. Do the regional differences arise from the pattern of overlap between the S1P1 receptor and activity of the gene for BDNF?
- Does bloodstream BDNF concentration reflect CNS BDNF concentration? Does fingolimod selectively increase brain BDNF?