his Viewpoint discusses the potential antiviral efficacy of fluoxetine in patients with enterovirus-D68–associated acute flaccid myelitis.
Enterovirus D68 (EV-D68) has emerged worldwide as an important cause of respiratory disease. Between mid-August 2014 and January 15, 2015, the Centers for Disease Control and Prevention confirmed 1153 cases of EV-D68–associated respiratory illness originating from 49 states. With this outbreak, there have been at least 107 cases of children presenting with acute flaccid myelitis associated with lesions identified on magnetic resonance imaging that were largely restricted to the spinal gray matter.1– 4 Children with this syndrome typically present with an acute febrile respiratory syndrome followed within 2 weeks by the development of acute flaccid myelitis, characterized by motor weakness, decreased tone and reflexes, and relatively preserved sensation. Weakness is of acute onset, preferentially affects upper limbs, and is often asymmetric. Cranial nerve involvement, including facial weakness, dysarthria, or dysphagia, may occur. Findings from the electrodiagnostic and magnetic resonance imaging studies are consistent with involvement of spinal cord motor neurons. Most patients have an associated cerebrospinal fluid pleocytosis. Paralysis has typically been prolonged and recovery incomplete. The exact role of EV-D68 in this syndrome has not been conclusively established, but approximately 50% of affected children have polymerase chain reaction–amplifiable EV-D68 RNA in nasopharyngeal or other upper respiratory tract secretions but not, to date, in cerebrospinal fluid.1,2,4
By stimulating microRNA miR-16 in the midline serotonergic raphe, fluoxetine initiates signaling cascades that lead to hippocampal neurogenesis.
Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has been unclear. These researchers studied the effects of fluoxetine in mice and in humans. They worked out several pathways that begin with the stimulation by fluoxetine of the microRNA miR-16 in serotonergic neurons in raphe and ultimately result in hippocampal neurogenesis.
In a series of experiments in mice, fluoxetine activated raphe miR-16, which decreased raphe levels of the serotonin reuptake transporter (SERT). In turn, these events directly caused brain-derived neurotropic factor (BDNF) and two other signaling molecules to act on the hippocampus. Indirectly, the same events resulted in release of another protein from the raphe nuclei, S100β, which in turn stimulated the locus coeruleus to induce SERT and secrete serotonin. Both the direct and indirect pathways caused decreases in hippocampal miR-16, which sequentially led to increases in both hippocampal SERT and the bcl-2 protein (which promotes neurotrophic function), which in turn stimulated neurogenesis. In nine patients with major depression, 12-week fluoxetine treatment increased levels of the three signaling molecules in cerebrospinal fluid. The interventions were accompanied by improvements in several mouse models of depression, as well as in the patients. See accompanying figure.
Comment: These findings draw together several seemingly unconnected lines of research. The authors identify miR-16 as a “missing link” between serotonin reuptake inhibitor treatment and hippocampal neurogenesis and as a “micromanager” of the intervening changes in the raphe nucleus, locus coeruleus, serotonin receptor transporter, serotonin secretion, and hippocampal neurogenesis. The processes appear to work through the cooperative and integrated activities of several signaling molecules. Further clarification of these pathways may help refine therapeutic strategies for depressive disorders.
Source: Journal Watch Psychiatry