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Pregabalin improves axon regeneration and motor outcome in a rodent stroke model.

ABSTRACT: Ischaemic stroke remains a leading cause of death and disability worldwide. Surviving neurons in the peri-infarct area are able to establish novel axonal projections to juxtalesional regions, but this regeneration is curtailed by a growth-inhibitory environment induced by cells such as reactive astrocytes in the glial scar. Here, we found that the astroglial synaptogenic cue thrombospondin-1 is upregulated in the peri-infarct area, and hence tested the effects of the anticonvulsant pregabalin, a blocker of the neuronal thrombospondin-1 receptor Alpha2delta1/2, in a mouse model of cortical stroke. Studying axonal projections after cortical stroke in mice by three-dimensional imaging of cleared whole-brain preparations, we found that pregabalin, when administered systemically for 5 weeks after stroke, augments novel peri-infarct motor cortex projections and improves skilled forelimb motor function. Thus, the promotion of axon elongation across the glial scar by pregabalin represents a promising target beyond the acute phase after stroke to improve structural and functional recovery.

SUBMITTER: Kugler C

PROVIDER: S-EPMC9443992 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Pregabalin improves axon regeneration and motor outcome in a rodent stroke model.

Kugler Christof C Blank Nelli N Matuskova Hana H Thielscher Christian C Reichenbach Nicole N Lin Tien-Chen TC Bradke Frank F Petzold Gabor C GC

Brain communications 20220627 4

Ischaemic stroke remains a leading cause of death and disability worldwide. Surviving neurons in the peri-infarct area are able to establish novel axonal projections to juxtalesional regions, but this regeneration is curtailed by a growth-inhibitory environment induced by cells such as reactive astrocytes in the glial scar. Here, we found that the astroglial synaptogenic cue thrombospondin-1 is upregulated in the peri-infarct area, and hence tested the effects of the anticonvulsant pregabalin, a ...[more]

PMID: 36072905

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Project description:The axon initial segment (AIS) generates action potentials and maintains neuronal polarity by regulating the differential trafficking and distribution of proteins, transport vesicles, and organelles. Injury and disease can disrupt the AIS, and the subsequent loss of clustered ion channels and polarity mechanisms may alter neuronal excitability and function. However, the impact of AIS disruption on axon regeneration after injury is unknown. We generated male and female mice with AIS-deficient multipolar motor neurons by deleting AnkyrinG, the master scaffolding protein required for AIS assembly and maintenance. We found that after nerve crush, neuromuscular junction reinnervation was significantly delayed in AIS-deficient motor neurons compared with control mice. In contrast, loss of AnkyrinG from pseudo-unipolar sensory neurons did not impair axon regeneration into the intraepidermal nerve fiber layer. Even after AIS-deficient motor neurons reinnervated the neuromuscular junction, they failed to functionally recover because of reduced synaptic vesicle protein 2 at presynaptic terminals. In addition, mRNA trafficking was disrupted in AIS-deficient axons. Our results show that, after nerve injury, an intact AIS is essential for efficient regeneration and functional recovery of axons in multipolar motor neurons. Our results also suggest that loss of polarity in AIS-deficient motor neurons impairs the delivery of axonal proteins, mRNAs, and other cargoes necessary for regeneration. Thus, therapeutic strategies for axon regeneration must consider preservation or reassembly of the AIS.SIGNIFICANCE STATEMENT Disruption of the axon initial segment is a common event after nervous system injury. For multipolar motor neurons, we show that axon initial segments are essential for axon regeneration and functional recovery after injury. Our results may help explain injuries where axon regeneration fails, and suggest strategies to promote more efficient axon regeneration.

Project description:BackgroundSpinal motoneurons may become hyperexcitable after a stroke. Knowledge about motoneuron hyperexcitability remains clinically important as it may contribute to a number of phenomena including spasticity, flexion synergies, and abnormal limb postures. Hyperexcitability seems to occur more often in muscles that flex the wrist and fingers (forearm flexors) compared to other upper limb muscles. The cause of hyperexcitability remains uncertain but may involve plastic changes in motoneurons and their axons.AimTo characterize intrinsic membrane properties of flexor carpi radialis (FCR) motor axons after stroke using nerve excitability testing.MethodsNerve excitability testing using threshold tracking techniques was applied to characterize FCR motor axon properties in persons who suffered a first-time unilateral cortical/subcortical stroke 23 to 308 days earlier. The median nerve was stimulated at the elbow bilaterally in 16 male stroke subjects (51.4 ± 2.9 y) with compound muscle action potentials recorded from the FCR. Nineteen age-matched males (52.7 ± 2.4 y) were also tested to serve as controls.ResultsAxon parameters after stroke were consistent with bilateral hyperpolarization of the resting potential. Nonparetic and paretic side axons were modeled by a 2.6-fold increase in pump currents (IPumpNI) together with an increase (38%-33%) in internodal leak conductance (GLkI) and a decrease (23%-29%) in internodal H conductance (Ih) relative to control axons. A decrease (14%) in Na+ channel inactivation rate (Aah) was also needed to fit the paretic axon recovery cycle. "Fanning out" of threshold electrotonus and the resting I/V slope (stroke limbs combined) correlated with blood potassium [K+] (R = -0.61 to 0.62, p< 0.01) and disability (R = -0.58 to 0.55, p < 0.05), but not with spasticity, grip strength, or maximal FCR activity.ConclusionIn contrast to our expectations, FCR axons were not hyperexcitable after stroke. Rather, FCR axons were found to be hyperpolarized bilaterally post stroke, and this was associated with disability and [K+]. Reduced FCR axon excitability may represent a kind of bilateral trans-synaptic homeostatic mechanism that acts to minimize motoneuron hyperexcitability.

Project description:Purpose: Penetrating eye injuries commonly cause permanent loss of vision in patients. Unlike mammals, zebrafish can regenerate both damaged tissue and severed axons in the central nervous system. Here, we present a tractable adult zebrafish model to study intraocular axon regeneration after penetrating eye injury. Methods: To create consistent penetrating intraocular injuries, pins of standardized diameters were inserted into the eye through the cornea and penetrating the retina but not the underlying sclera. Transgenic gap43:GFP reporter fish were used to preferentially label retinal ganglion cells (RGCs) that respond to injury with regenerating axons. Retinas were fixed and flat mounted at various times postinjury to examine injury size, number of green fluorescent protein (GFP)-positive cells and axons, axonal varicosities, and rate of regeneration to the optic nerve head. Intraocular injection of colchicine was used to inhibit axon outgrow as a proof of principle that this method can be used to screen effects of pharmacological agents on intraocular axon regeneration. Results: Penetrating injury to the zebrafish retina results in robust axon regeneration by RGCs around and beyond the site of injury. The gap43:GFP transgene allows visualization of individual or small bundles of axons with varicosities and growth cones easily observable. Regeneration proceeded with most, if not all, axons reaching the optic nerve head by 3-day postinjury. A single intraocular injection of colchicine a day after injury was sufficient to delay axon regeneration at 2-days postinjury. Surprisingly, we identified a stereotypically located population of circumferential projecting neurons within the retina that upregulate gap43:GFP expression after injury. Conclusions: Penetrating injury to the adult gap43:GFP transgenic zebrafish eye is a model of successful intraocular axon regeneration. The pharmacological and genetic tools available for this organism should make it a powerful tool for dissecting the cellular, molecular, and genetic mechanisms of axon regeneration in the intraocular environment.

Dataset Information

Pregabalin improves axon regeneration and motor outcome in a rodent stroke model.

Publications

Pregabalin improves axon regeneration and motor outcome in a rodent stroke model.

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