title: Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo.
abstract: FK-506 accelerates nerve regeneration and improves functional recovery in vivo; its immunosuppressive properties, however, limit its clinical utility. Geldanamycin (GA), a non-immunosuppressive agent, shares a common binding target (heat shock protein 90) with FK-506 and may accelerate nerve regeneration through a similar mechanism. GA has been shown to augment neurite outgrowth in vitro but has not been tested in vivo. The current study investigated the effect of GA on the rate of axonal regeneration and functional recovery following peripheral nerve injury. In the first experiment, Thy1-GFP transgenic rats underwent serial transmuscular imaging to quantify the rate of axonal regeneration following saphenous nerve crush injury. In subsequent experiments, Lewis rats underwent tibial nerve crush or transection-and-repair injuries and were assessed for functional recovery by walking track analysis. All animals were randomized to receive daily administration of FK-506 (2mg/kg), GA (0.2mg/kg), or a control vehicle (dimethyl sulfoxide, 1 mL/kg) starting 3 days prior to injury. Both GA and FK-506 significantly increased the rate of axonal regeneration following crush injury in Thy1-GFP rats. In Lewis rats undergoing tibial nerve crush injury, earlier functional recovery occurred at day 5 and day 6 in animals treated with FK-506 and GA respectively, vs. day 13 for controls. Over a truncated 21-day timeframe, Lewis rats undergoing tibial nerve transection-and-repair injury and treated with FK-506 regained function at day 16, whereas those treated with GA or the control vehicle did not regain normal function. GA-treated animals, however, did exhibit significant functional improvement vs. controls. The current study demonstrated that GA accelerates axonal regeneration and enhances functional recovery in vivo. Its ability to increase the rate at which peripheral axons regenerate is comparable to that of FK-506. GA, however, did not match the performance of FK-506 in injury models where Wallerian degeneration (WD) is ongoing in the distal stump. This provides evidence that FK-506 accelerates axonal regeneration through two parallel mechanisms: the first being its well-established effect on neurons; the second is likely a newly described, as-yet poorly defined mechanism that affects WD. Finally, given the decrease in observed toxicity with GA administration, it might be a suitable non-immunosuppressive alternative to FK-506 for accelerating peripheral nerve regeneration in cases of clinical nerve injury.
authors: Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8238, St. Louis, MO 63110, USA.
authors: H H
authors: HH
authors: Sun
authors: M
authors: M
authors: Saheb-Al-Zamani
authors: Y
authors: Y
authors: Yan
authors: D A
authors: DA
authors: Hunter
authors: S E
authors: SE
authors: Mackinnon
authors: P J
authors: PJ
authors: Johnson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D059348:Peripheral Nerve Injuries / Q000188:drug therapy* / Q000503:physiopathology*; D051381:Rats; D055647:Rats, Transgenic; D020127:Recovery of Function / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D007166:Immunosuppressive Agents; D047029:Lactams, Macrocyclic; D049452:Green Fluorescent Proteins; D016559:Tacrolimus; C001277:geldanamycin