Evaluation of Didox As a Potential Oral Therapy for MS

Background: Didox is a small unique polyphenol that has several biological activities including antiproliferation (T and B cell replication) and antioxidant and anti-inflammatory activities that could provide therapeutic benefit in MS.  In initial experiments using the MOG_35-55 induced chronic EAE mouse model for MS and intraperitoneal injection of the drug at a daily dose of 250 mg/kg, Didox delayed the onset and reduced the severity of symptoms as well as reversing established disease.

Objectives: Our objectives were to evaluate Didox as a potential treatment for MS, including whether it can be used as an oral treatment and to determine the mechanism of action of Didox in MS therapy.

Methods: To determine whether Didox is effective orally using the EAE model of MS, 550 mg/kg of the drug was administered by oral gavage daily using carboxymethyl cellulose as the carrier.

Results:  Oral Didox given prior to the onset of symptoms reduced the clinical score almost to baseline over a period of one week. When given either at the peak of symptoms or one week after the peak of symptoms, a similar reduction in clinical score was observed. The ability of oral Didox given at the peak of disease to reverse the clinical symptoms of chronic EAE was compared to BG-12 and mitoxantrone, all given orally.  The degree of recovery was identical except that the initiation of recovery by Didox was delayed by a few days. To gain insight into the mechanism of action of Didox, immune cells were isolated from the CNS of mice which had either been treated with Didox or vehicle alone (controls) at the time of maximal recovery from EAE.  Relative to untreated EAE mouse controls, the brains of Didox treated mice had decreased numbers of cd11b high/cd45.2 cells, which could represent a decrease of either activated macrophages/microglia or -/killer cells.   The brains of Didox treated mice had decreased numbers of activated killer cells as evidenced by decreased number of Cd11b high/NKp46 cells.  The spinal cords of Didox treated mice also had fewer active microglia and decreased numbers of TH 17 cells.  These immunological changes may account partially for the Didox-stimulated recovery of the EAE mice. 

Conclusions:  These data are consistent with the view that the biological activities of oral Didox could be beneficial in the treatment of MS.