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Serotonergic Stimulation of Optic Nerve Regeneration: A Potential Neurotherapeutic Platform for Peripheral Nerve Injury
Huseyin Karagoz, MD, PhD1; Fatih Zor, MD2; Yalcin Kulahci, MD3; Burcin Yavuz, PhD4; Fatma Nurefsan Selek, MD2; David L Kaplan, PhD4; Douglas Blackiston, PhD4; Michael Levin, PhD4; Vijay Gorantla, MD, PhD2
1Vanderbilt University Medical Center, Nashville, TN; 2Wake Forest Institute for Regenerative Medicine, Winston Salem, NC; 3Department of Hand and Upper Extremity Surgery, Wake Forest Institute for Regenerative Medicine, Winston Salem, NC; 4Tufts University, Medford, MA

Introduction: Neurons sense electrical cues from surrounding cells and initiate re-innervation. Recent studies have shown that serotonergic signaling modulates neural guidance and innervation. The FDA approved a 5-hydroxytryptamine receptor 1B/D (5-HT1B/D) agonist Zolmitriptan, targets macrophages to suppress inflammation. We performed a pilot study to stimulate regeneration after optic nerve (ON) transection/repair by using a sustained release Zolmitriptan platform.
Materials & Methods: The right ON of rats was transected behind the eyeball via a lateral orbital wall approach and repaired with 11/0 micro suture. Experimental animals (n=6) were treated with 5mg/mL zolmitriptan-loaded sonicated silk gel injected around the repair site of the ON following surgery, while controls (n=6) were not. Contralateral (untreated) eyes served as internal controls in all animals. At different time points (2, 4, and 6 weeks), animals were injected intraocularly with cholera toxin B fragment (CTB) for retrograde tracing of retinal axonal projections and imaged with microPET/CT prior to euthanasia. The total volume of interest (VOI), average of all VOI pixel values, and average of the highest number of hottest pixels values were quantified in microPET/CT.
Results: The site of ON transection injury (right) had more [11C]PBR28 uptake (itsí activity indirectly correlates with neuroinflammation) than the control side in all animals, and intensity decreased from 2nd to 6th weeks (Figure 1, yellow arrows) in the treated animal. Immunofluorescent labeled CTB tracing revealed significantly greater retinal projections beyond the injury site towards the chiasm (especially peripheral aspects of the nerves) with zolmitriptan treatment versus controls with no treatment (Figure 2).
Conclusions: Zolmitriptan improves ON regeneration and decreases neuroinflammation as confirmed by PET/CT and histopathology. Serotonin is abundant in the peripheral nerve tissues and may play a role in neuroprotective and neuroregenerative effects in the setting of peripheral nerve injury. Given its role in ON regeneration, we believe that sustained serotonergic stimulation may also optimize peripheral nerve regeneration.


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