2021 Volume 38 Issue 3 Pages 139-142
About a quarter–century ago, I encountered rat model of experimental autoimmune neuritis (EAN) for the first time in my life in Philadelphia where I stayed as a visiting scholar. Since then, I explored several experiments on EAN. As a president of the 38th annual meeting of the Japanese Society of Neurological Therapeutics, I would like to present what I had learned from rats with EAN and indicate the future perspective of developing new therapeutics for immune–mediated neuropathy (IMN).
Despite rapid progress of therapeutics for IMN, severe neurological sequelae or intractability still exist. To resolve these, EAN ; an animal model for IMN, is used. EAN is usually induced in Lewis rats to obtain uniform temporal profile of motor sign. About 10 days after immunization with peripheral nerve–related antigen, usually a synthetic peptide of bovine myelin P2 protein, monophasic motor paralysis develops, peaks about 5 days later and gradually recovers for next 10～15 days to reach mild sequelae. Activation of EAN is characterized by Th1 activity and at the peak of the disease Th1 to Th2 switching occurs, that finally results in spontaneous recovery. At peak stage of EAN, peripheral nerves are histologically characterized by severely infiltrated mononuclear phagocytes and lymphocyte and patchy foci of demyelination, that resolves considerably later.
To intervening pathological process of EAN, we tried several drugs that are already approved in treatment for non–neurological disorders, such as hyperlipidemia, hypertension or vasodilator, including hydroxymethylglutaryl–CoA reductase inhibitors (statins), angiotensin II receptor blockers (ARBs) and phosphodiesterase inhibitors (PDE–I).
We employed atorvastatin (ATO) ; one of strong statin that is able to suppress animal model of multiple sclerosis, various ARBs (candesartan ; CAN, losartan ; LO and irbesartan ; IRB), PDE3–I ; cilostazol (CLZ) and PDE5–I sildenafil (SIL).
ATO suppressed motor paralysis of EAN mildly and intraneural proinflammatory Th1 cytokine expression. But peak of anti–inflammatory Th2 cytokine expression was also suppressed and delayed, indicating ATO might suppress Th1 activity only.
IRB suppressed motor paralysis through entire EAN course while CAN did not suppress and LO delayed onset and accelerated recovery mildly. These differences clearly depended on the ARB's affinity to C–C chemokine receptor 2b.
CLZ suppressed EAN severity in entire course clinically and histologically via Th1 to Th2 deviation, while SIL facilitated recovery from motor paralysis indicating remyelination and regeneration of the peripheral nerve.
The disease modifying ability of all the drugs I depicted above seems insufficient to treat human patients when used single, however these drugs might be useful if used in combination with any other treatment. Further study is needed to elucidating this point in future.
