Permanent neurological deficits in inflammatory and toxic neuropathic conditions are closely related to the degree of axonal injury. The underlying pathomechanisms that link endoneural inflammation and toxicity to axonal degeneration are incompletely understood. Our group aims to define the reciprocal interactions of endoneural inflammation and toxic compounds to axonal injury and to translate these findings into new therapeutic approaches in pre-clinical and early clinical studies.
Our group is interested in pathomechanisms of axonal injury and impaired regeneration in diseases of the peripheral nervous system. These encompass a spectrum of prevalent, often severe disabling, heterogeneous disorders of inflammatory, toxic, hereditary or metabolic origin. Patients with peripheral neuropathy often display severe motor deficits with significant disability, especially after a prolonged disease course. There is clinical evidence that the disability and poor prognosis in those diseases is invariably associated with axonal injury and impaired axonal regeneration of affected nerve fibers. It is assumed that disease specific mechanisms actively prevent axons from their successful regeneration. Critical mediators of axonal injury that have been identified include pro-inflammatory cytokines such as TNF-alpha and the free radical nitric oxide (NO), which is released by endoneural macrophages. Moreover there is experimental evidence that antibodies against gangliosides which are autoimmune markers in Guillain-Barré syndrome (GBS) can impair axon regeneration and nerve repair. In previous studies we could demonstrate that the inhibition of neurite outgrowth mediated by anti-ganglioside antibodies involves the activation of the RhoA and ROCK pathway by engagement of specific cell-surface gangliosides. These data implicate that the modulation of RhoA and ROCK may represent a promising target for novel therapeutic approaches to enhance axonal regeneration in peripheral nerve disorders. Furthermore we are characterizing the role of mitochondria as critical determinants for axonal maintenance in neuroinflammatory and neurotoxic conditions. The translation of these findings to improved diagnostic measures and novel therapeutic approaches on a pre-clinical and early clinical stage represents another research topic of our group. To address these issues we are currently exploring the role of dysfunctional axonal mitochondria in in vitro and in vivo models of neuroinflammation and chemotherapeutic induced toxicity in the peripheral nervous system. Furthermore in reverse translational approaches we investigate the role of autoantibodies in axonal damage in immune mediated neuroinflammatory diseases like GBS or chronic inflammatory demyelinating polyneuropathy (CIDP).
Immune neuropathies are acute or chronic immune mediated inflammatory neuropathies, which can be distinguished by clinical symptoms, electrophysiology and autoantibody profiles. One area of interest is the role of antibodies against neuronal antigens in the pathogenesis of axonal and demyelinating GBS. Another focus of our research are mechanisms of action by which intravenous immunoglobulins can neutralize autoantibodies. In a recent study we explored the role of newly formed IgG dimers after IVIg treatment and could demonstrate that those dimeric IgG fractions contain autoantibodies and their anti-idiotypes. In future experiments we will explore kinetics of IgG dimers in animal models and the specificity of these antibodies.
Furthermore we are exploring the underlying causes of failed nerve regeneration in immune neuropathies. For this purpose we established an animal model of chronic nerve denervation in which we assess the plasticity of conditioned Schwann cells in order to understand the impact of inflammation on the regenerative function of Schwann cells.
About thirty percent of all cancer patients receiving chemotherapy suffer from chemotherapy-induced peripheral neuropathy (CIPN), which makes CIPN to one of the most significant side effects of many widely used antineoplastic drugs. CIPN is often dose limiting and severely affects the quality of life in cancer survivors. We are exploring in in vitro and in vivo models the pathogenesis of CIPN. Recent findings from our lab indicate that dysfunction of axonal mitochondria is essential for the pathogenesis of paclitaxel and cisplatin induced neuropathy. As contributing factor we identified defective axonal transport mechanism of mRNA which alter fusion and fission of axonal mitochondria in distal nerve segments. In further studies we are currently exploring how paclitaxel enters the peripheral nervous system. The aim is to modulate the access of paclitaxel and other antineoplastic compounds to peripheral nerves in order to prevent CIPN.
ALS is a progressive motor neuron disease in which the pathogenesis is incompletely understood. It is assumed that mitochondrial dysfunction and inflammatory processes result in degeneration of motor neurons. We explore in vitro and in vivo models novel therapeutic approaches to support the regeneration of motor neurons in order to ameliorate the disease course in humans.
The overall goal of our group is to get deeper insights into the pathogenesis of peripheral neuropathies in order to improve diagnostic and treatment in this group of disorders. Regarding immune neuropathies we are optimistic that our research will result in the development of novel body fluid and imaging surrogate markers. By our research in CIPN we learned that the most promising approach to prevent CIPN is to limit the access of these compound to the PNS right away. The future characterisation of the transport mechanism holds thus great promise to prevent this clinically relevant side effect.
Ritter, C., Bobylev, I., Lehmann, H.C. (2015) Chronic inflammatory demyelinating polyneuropathy (CIDP): change of serum IgG dimer levels during treatment with intravenous immunoglobulins. J Neuroinflammation 12:148
Bobylev, I., Joshi, A.R., Barham, M., Ritter, C., Neiss, W.F., Höke, A., Lehmann, H.C. (2015) Paclitaxel inhibits mRNA transport in axons. Neurobiol Dis 82:321-31.
Joshi A.R., Bobylev, I., Zhang, G., Sheikh, K.A., Lehmann, H.C. (2015) Inhibition of Rho-kinase differentially affects axon regeneration of peripheral motor and sensory nerves. Exp Neurol 263: 28-38.
Joshi, A.R., Muke, I., Bobylev, I., and Lehmann, H.C. (2019). ROCK inhibition improves axonal regeneration in a preclinical model of amyotrophic lateral sclerosis. J Comp Neurol 527, 2334-40.
Bobylev I, Joshi AR, Barham M, Neiss WF, and Lehmann HC (2018). Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. Mol Neurobiol 55, 1227-1235.
Wunderlich G, Brunn A, Daimaguler HS, Bozoglu T, Fink GR, Lehmann HC, Weis J, and Cirak S (2018). Long term history of a congenital core-rod myopathy with compound heterozygous mutations in the Nebulin gene. Acta Myol 37, 121-127.
Wunderlich G, Abicht A, Brunn A, Daimaguler HS, Schroeter M, Fink GR, Lehmann HC, and Cirak S (2018). [Congenital myasthenic syndromes in adulthood: Challenging, rare but treatable]. Nervenarzt10.1007/s00115-018-0562-9.
Bobylev, I., Joshi, A.R., Barham, M., Neiss, W.F., and Lehmann, H.C. (2018). Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. Mol Neurobiol 55, 1227-35.
Ritter, C., Svacina, M.K., Bobylev, I., Joshi, A., Schneider, T., and Lehmann, H.C. (2017). Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study. J Neuroimmune Pharmacol 12, 204-9.
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Maryam Balke (MD)
lja Bobylev (post doc)
Claudia Drapatz (technician)
Nora Hager (medical student)
Abhijeet Joshi (PhD student)
Ines Klein (PhD student)
Christian Ritter (MD)
Christian Schneider (MD)
Christoph Seifert (MD)
Alina Sprenger (medical student)
Martin Svacina (medical student)