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@ARTICLE{Griffin:249930,
      author       = {Griffin, Jarred and Hingorani Jai Prakash, Sonia and
                      Bockemühl, Till and Benner, Jessica M and Schaffran,
                      Barbara and Moreno-Manzano, Victoria and Büschges, Ansgar
                      and Bradke, Frank},
      title        = {{R}ehabilitation enhances epothilone-induced locomotor
                      recovery after spinal cord injury.},
      journal      = {Brain communications},
      volume       = {5},
      number       = {1},
      issn         = {2632-1297},
      address      = {[Großbritannien]},
      publisher    = {Guarantors of Brain},
      reportid     = {DZNE-2023-00245},
      pages        = {fcad005},
      year         = {2023},
      abstract     = {Microtubule stabilization through epothilones is a
                      promising preclinical therapy for functional recovery
                      following spinal cord injury that stimulates axon
                      regeneration, reduces growth-inhibitory molecule deposition
                      and promotes functional improvements. Rehabilitation therapy
                      is the only clinically validated approach to promote
                      functional improvements following spinal cord injury.
                      However, whether microtubule stabilization can augment the
                      beneficial effects of rehabilitation therapy or act in
                      concert with it to further promote repair remains unknown.
                      Here, we investigated the pharmacokinetic, histological and
                      functional efficacies of epothilone D, epothilone B and
                      ixabepilone alone or in combination with rehabilitation
                      following a moderate contusive spinal cord injury.
                      Pharmacokinetic analysis revealed that ixabepilone only
                      weakly crossed the blood-brain barrier and was subsequently
                      excluded from further investigations. In contrast,
                      epothilones B and D rapidly distributed to CNS compartments
                      displaying similar profiles after either subcutaneous or
                      intraperitoneal injections. Following injury and
                      subcutaneous administration of epothilone B or D, rats were
                      subjected to 7 weeks of sequential bipedal and quadrupedal
                      training. For all outcome measures, epothilone B was
                      efficacious compared with epothilone D. Specifically,
                      epothilone B decreased fibrotic scaring which was associated
                      with a retention of fibronectin localized to perivascular
                      cells in sections distal to the lesion. This corresponded to
                      a decreased number of cells present within the intralesional
                      space, resulting in less axons within the lesion. Instead,
                      epothilone B increased serotonergic fibre regeneration and
                      vesicular glutamate transporter 1 expression caudal to the
                      lesion, which was not affected by rehabilitation.
                      Multiparametric behavioural analyses consisting of
                      open-field locomotor scoring, horizontal ladder, catwalk
                      gait analysis and hindlimb kinematics revealed that
                      rehabilitation and epothilone B both improved several
                      aspects of locomotion. Specifically, rehabilitation improved
                      open-field locomotor and ladder scores, as well as improving
                      the gait parameters of limb coupling, limb support, stride
                      length and limb speed; epothilone B improved these same gait
                      parameters but also hindlimb kinematic profiles. Functional
                      improvements by epothilone B and rehabilitation acted
                      complementarily on gait parameters leading to an enhanced
                      recovery in the combination group. As a result, principal
                      component analysis of gait showed the greatest improvement
                      in the epothilone B plus rehabilitation group. Thus, these
                      results support the combination of epothilone B with
                      rehabilitation in a clinical setting.},
      keywords     = {axon regeneration (Other) / epothilone (Other) /
                      neuroplasticity (Other) / rehabilitation (Other) / spinal
                      cord injury (Other)},
      cin          = {AG Bradke},
      ddc          = {610},
      cid          = {I:(DE-2719)1013002},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36744011},
      pmc          = {pmc:PMC9893225},
      doi          = {10.1093/braincomms/fcad005},
      url          = {https://pub.dzne.de/record/249930},
}