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

Abstract

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 α-synuclein (H-αSynOs). 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-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs 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-αSynOs-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-αSynOs 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-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs 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.

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex

“…The in vivo protocol used in the present study is based on a previously validated PD model, where the unilateral H-αSynOs infusion reproduced the motor symptomatology and the underlying progressive neuropathology, including dopaminergic degeneration, persistent neuroinflammation in motor-related areas as well as systemic immune dysregulation, deposition and spreading of p-αSyn outside the infusion site [ 27 ]. Moreover, the predictive validity as a translational PD model to test disease-modifying compounds has been recently reported [ 29 ]. Here, a bilateral infusion protocol was adopted in order to avoid any contralateral compensation in cognition tasks.…”

“…In addition, the inter-relationship between α-Syn toxicity, neuroinflammation and cognitive decline has never been investigated in rodents, mainly due to the unavailability of a valid preclinical neuropathological PD model that recapitulates cognitive symptoms. In previous studies, we have shown that the intranigral infusion of H-αSynOs induced an intense neuroinflammatory response in motor areas including the SN and the nucleus striatum [ 27 , 29 ]. Here, we reported that the H-αSynOs infusion triggered a glial response in cortical regions typically involved in cognitive impairment in humans, including the ACC and hippocampus.…”

“…and medetomidine hydrochloride (0.33 mg/kg, i.p. ), 5 µL of H-αSynOs were stereotaxically injected bilaterally into the substantia nigra pars compacta (SNpc) at the rate of 1 µL/min via a silica microinjector, as previously described (coordinates relative to bregma; −5.4 mm anteroposterior; ±1.9 mm from the midline; −7.2 mm beneath the dura, according to the atlas of Paxinos and Watson) [ 27 , 29 , 33 ]. Control animals received an equal volume of sterile phosphate buffer saline (PBS, pH 7.4) at the same infusion rate ( Figure 1 ).…”

“…A main reason for the poor knowledge of MCI neuropathology is the lack of a preclinical neuropathological model that may reproduce both the classical motor dysfunction and the non-motor cognitive symptoms. In recent years, a novel translational model of PD neuropathology has been developed, based on the intracerebral infusion of in vitro-generated human α-Syn oligomers (H-αSynOs) [ 27 , 28 , 29 ], according to the evidence that soluble small oligomeric species are the most toxic form of this protein [ 30 , 31 , 32 ]. The H-αSynOs model progressively develops motor deficits, and displays a typical α-Syn-induced neuropathology, including the spreading and aggregates of phosphorylated α-Syn (p-αSyn) and a chronic unremitting neuroinflammation in basal ganglia structures primarily involved in the motor pathology, along with a systemic inflammatory status [ 27 , 29 ].…”