Thalidomide Derivatives for the Treatment of Neuroinflammation

Abstract

The precise mechanism-of-action of thalidomide remains uncertain and might differ between diseases and under different clinical condition. With implications in the treatment of a variety of inflammatory and autoimmune diseases, as well as for use as an anticancer agent, alone or in combination with established therapeutics, it is clear that thalidomide and its derivatives deserve further scrutiny. In particular, thalidomide was shown to be effective in a mouse model of multiple sclerosis (MS), an autoimmune inflammatory disorder, called experimental autoimmune encephalomyelitis (EAE). Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit EAE was investigated, and it was shown that, at 100 mg kg⁻¹ thalidomide-equivalent dose, they abrogated the clinical and pathological features of EAE.

Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity

“…While a therapeutic effect of lenalidomide in an MS model has not been reported previously, thalidomide treatment has been shown to delay EAE symptom onset and reduced symptom severity (Contino-Pepin et al, 2009, Contino-Pepin et al, 2010, Correa et al, 2010). Initially thalidomide was shown to be a TNFα inhibitor, but it has more recently been found to possess additional immune modulatory actions, partly by influencing NF-κB activation and several anti-apoptotic proteins (Vallet et al, 2008).…”

“…Lenalidomide also increases the production of interferon-γ, IL-10 and IL-2, and modulates natural killer cell and antibody-dependent cellular cytotoxicity (Kotla et al, 2009, Zhu et al, 2013). While clinical trials of thalidomide or lenalidomide in MS patients have not been performed, thalidomide was reported to reduce inflammation and delay symptom onset in an experimental autoimmune encephalomyelitis (EAE) animal model (Sastry, 1999, Contino-Pepin et al, 2009, Contino-Pepin et al, 2010, Correa et al, 2010). Although lenalidomide treatment has not previously been tested in the EAE model, it has been reported to attenuate degeneration of motor neurons in a mouse model of amyotrophic lateral sclerosis (Neymotin et al, 2009).…”

Evaluation of the Anti-Schistosoma mansoni Activity of Thiosemicarbazones and Thiazoles

“…They also activate the Th1 response, by increasing gamma interferon (IFN-␥) and IL-2, have antiangiogenic and antiproliferative properties, activate apoptosis, T cells, and NK cells, and inhibit cell adhesion (37,38).…”

From Electronic Waste to Suzuki−Miyaura Cross‐Coupling Reaction in Water: Direct Valuation of Recycled Palladium in Catalysis

“…TAC surfactants are obtained in a single step by free radical polymerization of an acryloyl monomer derived from tris(hydroxymethyl)acrylamide-methane (THAM) in the presence of an alkane-or a perfluoroalkanethiol as a transfer reagent (telogen), and have been prepared at the gramscale. [36] These oligomers, perfectly water soluble for average degrees of polymerization (DPn ≥ 4), have been developed for variable applications from drug delivery [37,38] and theranostics [39] to extraction and stabilization of membrane proteins. [40] We focused in the present study on two molecules of this family (Figure 2), a fluorinated one (F-TAC, with a C 6 F 13 CH 2 CH 2 chain) and a hydrogenated one (H-TAC, with a C 12 H 25 chain).…”