Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human ?-synuclein (H-?SynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-?SynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-?SynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-?SynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-?SynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-?SynOs infusion as well as after H-?SynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-?SynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-?. In contrast, pomalidomide inhibited the TNF-? overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-?SynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.