Dietmar Fischer

A high-throughput screening led to the discovery of cyclic pentapeptides binding to the CK2β-site of both CK2α and CK2α′. These compounds disturb the assembly of both CK2α ₂ β ₂ and CK2α′ ₂ β ₂ holoenzymes and induce holoenzyme dissociation.

Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor–deficient db/db mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)–dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.

Traumatic peripheral nerve injuries frequently result in irreversible functional deficits. While neurons possess an intrinsic capacity for axonal regeneration, the temporal constraints and the slow pace of neurite outgrowth often impede the complete restoration of sensory and motor capabilities. This impairment, often culminating in chronic disability, represents a significant clinical challenge, as there are currently no approved pharmacological interventions available to accelerate axon regeneration and improve functional recovery. This perspective focuses on recent scientific advancements that have identified sesquiterpene lactones, a family of naturally derived plant metabolites, as potential therapeutic candidates for treating peripheral nerve trauma. Preclinical investigations employing parthenolide and cnicin have revealed that these compounds can substantially augment axonal extension and functional recovery in diverse in vivo animal paradigms and primary human neuronal cultures. The favorable bioavailability of cnicin following oral administration, coupled with its notable tolerability at dosages considerably largely surpassing the therapeutic range, underscores its substantial potential as an effective pharmacological treatment for addressing the challenges associated with nerve regeneration and restoring sensory and motor functions.

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Treatments accelerating axon regeneration in the nervous system are still clinically unavailable. However, parthenolide promotes adult sensory neurons’ axon growth in culture by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration. At the same time, the partial knockdown of endogenous vasohibins or their enhancer SVBP in neurons facilitates axon growth, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-amino-parthenolide (DMAPT) markedly facilitates the regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves, leading to acceleration of functional recovery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT the first promising drugs for curing nerve injury.

Experimental autoimmune neuritis is a common animal model for acute human immune–mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P2_53–78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage.