Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis

Abstract

Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey-Hair test, electrophysiological, qPCR, and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey-Hair test, flow cytometric, and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at days 0, 4, 8, and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of NFKB. Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes, that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.

Small fibre integrity and axonal pathology in the rat model of experimental autoimmune neuritis

“…The involvement of the small nerve fibre and altered pain sensation was previously detected in the EAN by our group, 21 and we reproduced these results in our current experiments. Changed integrity of small nerve fibres is associated with nociception.…”

“…A previous study from our group determined the involvement of small nerve fibres in the EAN by detecting alterations in nociception, more precisely, mechanical hyperalgesia over the disease course. 21 The performed Hargreaves and vF hair tests depicted an acute pain oversensitivity to mechanical and thermal stimuli, reaching its peak concordant with motor symptoms on Day 15 p.i. (Hargreaves test: P -value < 0.0001; Fig.…”

“… 19 , 20 A development of EAN-induced hyperalgesia was previously identified from our group in EAN, indicating the involvement of the small nerve fibres. 21 …”

Kinesin-5 inhibition improves neural regeneration in experimental autoimmune neuritis

“…Regarding the positive and negative sensory deficits displayed in GBS and EAN, Wei et al [ 16 ] found compelling evidence that kinesin-5 inhibition reversed pathological pain by inhibiting vanilloid receptor subtype 1 (VR1) axonal trafficking. Painful sensory deficits also occur during autoimmune neuritis, indicating another possible potential indication for monastrol [ 60 ]. This warrants further investigations, which should not only include a thoroughly motor behavioural testing, but also testing of the sensory function for pain, temperature and touch.…”

Novel Immunotherapies for Myasthenia Gravis

“…The propensity for neuropathy is diminished by restricting the dose to a single cycle of bortezomib which appears sufficient to induce remission in immunological diseases and by adopting subcutaneous rather than intravenous route of administration. 92 …”