Objective: This review aims to analyze studies on the implication of S100B in Parkinson’s Disease (PD) and shed light on Pentamidine as a novel treatment in the field of disease therapeutics.

Background: PD is characterized by a loss of dopaminergic neurons and the accumulation of α-synuclein in neurons in the brainstem and cortical regions [1]. Evidence has shown increased levels of S100B – a calcium-binding protein secreted by astrocytes- contributes to the pathogenesis of PD, mainly by regulating neuroinflammation and dopamine metabolism. Pentamidine, is an antiprotozoal drug that directly blocks S100B activity [2].

Method: A literature search was conducted on PubMed and Google Scholar databases for English, peer-reviewed articles and reviews published between January 2000-January 2021. Search terms were: “neuroinflammation AND Parkinson’s disease”, “S100B AND Parkinson’s disease”, “Pentamidine AND S100B”. Case reports were excluded. Focus was placed on animal- or human-based studies.

Results: S100B has shown to contribute to neurodegeneration in animal models of PD. In vitro studies revealed that elevated S100B was associated with increased glial cell proliferation and reduced neuronal survival [3]. Other experimental studies showed S100B overexpression in transgenic mice caused motor deficits through inhibition of dopamine D2 receptor expression and promotion of oxidative stress with secretion of pro-inflammatory cytokines [4]. Moreover, S100B promoted the proinflammatory M1 phenotype microglia and inhibited the anti‑inflammatory M2 phenotype causing cerebral ischemia [5]. In post-mortem human studies, S100B levels were increased in the substantia nigra and the dorsomedial prefrontal cortex of patients with PD compared to those without PD [1] Clinically, elevated serum S100B levels resulted in increased disease severity with respects to motor symptoms in PD patients [6]. However, Pentamadine, a S100B inhibitor, has shown to ameliorate motor deficits in transgenic mice [7]. In addition, studies have revealed the drug has prevented dopaminergic neuronal loss and neuroinflammation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice.

Conclusion: Emerging evidence suggests S100B mediates the pathogenesis of PD and is a potential therapeutic target against the disease. Therefore, Pentamdine, a S100B inhibitor seems promising in the treatment of PD. Limitations, implications, and future directions for research are discussed.

References: 1) Sathe K et al (2012) S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain 135(Pt 11):3336–3347 2) Di Sante, G., Amadio, S., Sampaolese, B., Clementi, M. E., Valentini, M., Volonté, C., Casalbore, P., Ria, F., & Michetti, F. (2020). The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing-Remitting Multiple Sclerosis Mouse Model. Cells, 9(3), 748. https://doi.org/10.3390/cells9030748 3) Brozzi, F., Arcuri, C., Giambanco, I., & Donato, R. (2009). S100B Protein Regulates Astrocyte Shape and Migration via Interaction with Src Kinase: IMPLICATIONS FOR ASTROCYTE DEVELOPMENT, ACTIVATION, AND TUMOR GROWTH. The Journal of biological chemistry, 284(13), 8797–8811. https://doi.org/10.1074/jbc.M805897200 4) Businaro R et al (2006) S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses. J Neurosci Res 83(5):897–906 5) Zhou S et al (2018) S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia. Inflamm Res 67(11–12):937–949 6) Cunha MP et al (2017) MPP(+)-lesioned mice: an experimental model of motor, emotional, memory/learning, and striatal neurochemical dysfunctions. Mol Neurobiol 54(8):6356–6377. 7) Rinaldi F et al (2019) inPentasomes: An innovative nose-to-brain pentamidine delivery blunts MPTP parkinsonism in mice. J Control Release 294:17–26

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