Cyclosporin A Affects Axons and Macrophages During Wallerian Degeneration

Abstract

A traumatic injury of a peripheral nerve leads to Wallerian degeneration. It includes the recruitment of macrophages and the phagocytosis of myelin and the remnants of axons. We have previously studied the recruitment of macrophages and now wished to determine if the immunosuppressant cyclosporin A (CsA) affects the number of macrophages at the site of nerve injury. The primary target of CsA is T-cells, but it may also have an effect on mononuclear phagocytes which exert a key role during Wallerian degeneration. Rats were divided into two groups: CsA-treated animals and control animals. Following transection of the sciatic nerve in the treatment group, the animals received 5 mg/kg CsA subcutaneously. The groups were further subdivided into a freely regenerating nerve group and a sutured nerve group. The number of macrophages and MHC class II positive cells were counted 3 days, 7 days, 2 weeks, 4 weeks, and 8 weeks posttransection; also CD4, CD8, IL-2 receptor positive cells, B cells, and the axonal sprouting were studied. In the CsA-treated group, there were more macrophages in the distal areas under 8 weeks than in the controls (p < 0.05); thus, the clearance of macrophages is delayed in the CsA-treated rats compared to the control rats. In the proximal area, the difference in macrophage number did not gain statistical significance. Additionally, CsA retarded axonal degeneration. CsA affects number of macrophages during Wallerian degeneration, while retarding axonal degeneration and subsequent reinnervation. Its mechanism of action appears to involve either direct or indirect via T-cells-mediated responses.

Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore

“…Previous studies suggested that in vivo treatment with CsA delays axonal degeneration in the PNS (Sunio and Bittner, 1997; Taskinen and Röyttä, 2000), however this was attributed to immunosuppression rather than any direct effects on the neuronal mitochondria. Genetic inactivation of CypD was also shown to reduce axonal damage and disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (Forte et al, 2007).…”

“…Notably, deletion of the murine CypD gene reduces axonal degeneration in an autoimmune encephalomyelitis model (Forte et al, 2007), and treatment of animals with CsA protects against Wallerian degeneration (Sunio and Bittner, 1997; Taskinen and Röyttaä, 2000). CsA can inhibit the mPTP through its interaction with CypD, but it also has immunosuppressant actions through calcineurin inhibition (Liu et al, 1991).…”

The endoneurial response to microsurgically removed epi‐ and perineurium

“…The paraffin sections were pretreated using the procedure described above for Schwann cells and the sections were treated with the 1:200 monoclonal antibody against neurofilament (Euro‐Diagnostica 031.03 MNF). Bound antibodies were demonstrated using an avidin‐biotin method with a Vectastain ABC Kit according to the instructions of the manufacturer ( Taskinen and Röyttä, 2000 ) .…”

Effect of cyclosporin A on immunological response in lungs of guinea pigs infected with Trichinella spiralis.

“…To our knowledge there are no data concerning the effects of CsA on cellular infiltration in the lungs. In other tissues increased accumulation of macrophages and granulocytes after CsA treatment has been reported (Dick et al, 1997;Taskinen & Roytta, 2000). Most studies were dealing with the effects of CsA on the antigen-induced immunological response, expressed mainly by eosinophil infiltration, induced in the lungs in vivo or in vitro.…”