Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury

Abstract

Microtubule stabilisation 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 seven weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared to epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localised 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 fiber 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 complementary on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed a greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

Do Pharmacological Treatments Act in Collaboration with Rehabilitation in Spinal Cord Injury Treatment? A Review of Preclinical Studies

“…While both drugs were effectively distributed through the blood–brain barrier, epothilone B exerted a higher effect in reducing fibrotic scarring and the number of cells and axons within the lesion and increasing serotonergic fiber regeneration and VGLUT1 distal to the lesion irrespective of rehabilitation. Thus, they concluded that epothilone B and rehabilitation acted complementarily, leading to an enhanced gait recovery [ 73 ].…”

Genetically modified peripheral neurons transplant aided activity maintenance and secretome modulation: a novel strategy for spinal cord injury treatment

“…Additionally, it significantly improved serotonergic regeneration and increased vesicular glutamate transporter 1 (VGLUT1) excitatory input into central pattern generator, thereby improving functional recovery. In combination with rehabilitation, all of these parameters were further enhanced [120].…”

“…Consequently, several therapeutic approaches for SCI focus on the maintenance and generation of activity in the spinal cord. Several studies highlight the link between exercise induced activity which is capable of improving axonal regeneration [179], associated with an increase in the expression of pre-synaptic markers [184,185], and specifically, pre-synaptic excitatory markers such as VGLUT1 [120,186]; and vesicular glutamate transporter 2 (VGLUT2) [110,187]. While the exact mechanism behind exercise induce locomotor function…”

“…Since cytoskeleton modulating drug Epothilone B has been described to enhance neuronal length in vitro [96], as well as in vivo [119,120] , and Blebbistatin has been shown previously to improve axonal length [117,118,125,250]; our first objective was to observe if there was a synergistic effect by the application of both drugs that act upon different components of the growth cone cytoskeleton, microtubules and NMMII. We first verified that the non-permissive chondroitin sulphate proteoglycans (CSPGs) did indeed create an inhibitory environment and reduced neurite length and outgrowth, like that found in the environment surrounding the injury.…”

“…Several studies have shown that microtubule stabilising drugs such as Taxol, Epothilone B can promote axonal extension [96,253] (Figure 11B). Use of Epothilone has also been shown to have positive results in vivo in SCI models, however it is now believed it is due to the effect dual effect on other cell types due to effects such as reduced fibrotic scarring rather than only axonal extension of neurons [120,254].…”