Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons. The cell bodies of these neurons are present in the substantia nigra, with the nerve terminals being in the striatum. Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these. Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway. Characteristic of neuroinflammation is the activation of brain glial cells, principally microglia and astrocytes that release various soluble factors. Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons. Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD. All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and, when measured, preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals. Some of these agents were shown to exert an anti-inflammatory action, decrease oxidative stress, and reduce lipid peroxidation products. Activation of microglia and astrocytes was also decreased, as well as infiltration of T cells into the substantia nigra. Pretreatment with fingolimod, tanshinoine I, dimethyl fumarate, thalidomide, or cocaine- and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals. Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk, including genetic factors.

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

“…To our knowledge, this is the first report evaluating POM as a neuroprotective agent in a PD model. Moreover, this is the first report on the efficacy of an immunomodulatory drug in a transgenic model of PD, which complement studies investigating the neuroprotective efficacy of these agents in toxin-based or alpha-synuclein-based models (Martinez and Peplow, 2018).…”

“…Based on the recognized role of neuroinflammation and inflammatory cytokines in the neuropathology of PD, clinically available agents that act on the central immune system via an immunosuppressive or immunomodulatory mechanism have been tested in experimental models of PD (Martinez and Peplow, 2018). Among drugs in clinical use, the immunosuppressants Fingolimod (Gilenya), Tacrolimus (Fujimycin) and Cyclosporin have been reported as effective neuroprotective treatments in rodent models of dopaminergic degeneration (Tamburrino et al, 2015;Van der Perren et al, 2015;Vidal-Martínez et al, 2016;Ren et al, 2017;Zhao et al, 2017).…”

“…Dimethyl Fumarate, another FDA-approved drug with a mixed mechanism of action that includes an anti-inflammatory activity, was reported effective in ameliorating PD features in an alpha-synuclein based model of PD (Lastres-Becker et al, 2016). More recently, the focus of research for the treatment of neurological disorders has moved toward the investigation of agents acting through an immunomodulatory, rather than immunosuppressive mechanism (Martinez and Peplow, 2018). Hence, given the dual beneficial and potentially harmful roles of activated immune cells within the CNS, the strategy of boosting reparative and protective functions, while suppressing pro-inflammatory activity and the detrimental effects of inflammatory cytokines, might be efficacious to achieve neuroprotection in PD (Frankola et al, 2011;Lecca et al, 2018).…”

“…On the contrary, in the case of PD, deregulation of neuroinflammatory responses occurs, and the chronic release of inflammatory cytokines, such as tumor necrosis factor (TNF)-α, is regarded as a principal pathological contributor to the ensuing progressive neurodegeneration (Joers et al, 2017). In this light, pharmacologically targeting the mechanisms underpinning cytokine production or actions may provide a compelling disease-modifying strategy for PD (Martinez and Peplow, 2018).…”

“…Based on the recognized role of neuroinflammation in PD neuropathology, evaluating commercially available immunomodulatory drugs for repositioning in PD has been considered an auspicious approach (Martinez and Peplow, 2018). Different classes of clinically available drugs active on the immune system have been investigated across various experimental models of PD, suggesting a benefit in slowing the disease progression and the development of motor symptoms (Van der Perren et al, 2015;Ren et al, 2017;Zhao et al, 2017).…”