Pre-clinical Studies Identifying Molecular Pathways of Neuroinflammation in Parkinson's Disease: A Systematic Review

Abstract

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra of the brain. In this review, we summarize evidence obtained by animal studies demonstrating neuroinflammation as one of the central pathogenetic mechanisms of PD. We also focus on the protein factors that initiate the development of PD and other neurodegenerative diseases. Our targeted literature search identified 40 pre-clinical in vivo and in vitro studies written in English. Nuclear factor kappa B (NF-kB) pathway is demonstrated as a common mechanism engaged by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), as well as the bacterial lipopolysaccharide (LPS). The α-synuclein protein, which plays a prominent role in PD neuropathology, may also contribute to neuroinflammation by activating mast cells. Meanwhile, 6-OHDA models of PD identify microsomal prostaglandin E synthase-1 (mPGES-1) as one of the contributors to neuroinflammatory processes in this model. Immune responses are used by the central nervous system to fight and remove pathogens; however, hyperactivated and prolonged immune responses can lead to a harmful neuroinflammatory state, which is one of the key mechanisms in the pathogenesis of PD.

Keywords: NLRP3 inflammasome; Parkinson's disease; mast cells; microglia; neuroinflammation; nuclear factor kappa B (NF-κB).

Figure 1

PRISMA 2020 flow diagram for systematic reviews which included searches of databases.

Figure 2

Servier (2022) mechanisms involved in PD pathogenesis. In this figure, the mechanisms following MPTP exposure through which dopaminergic cell death occurs are illustrated. The active metabolite of MPTP, MPP⁺, is produced in glial cells and transfers into dopaminergic neurons via DA transporter. In the neuron, this activated metabolite causes synaptic dysfunction as well as mitochondrial dysfunction which triggers aggregation of α-Syn. It also can lead to neuroinflammation and microglial activation. Acting together, the mentioned mechanisms can lead to dysfunction of BBB, which is one of the main pathological findings in PD, in addition to Lewy bodies and α-Syn aggregation.

Figure 3

Servier (2022) the neuroinflammatory cascade mediated by NF-κB. TNF-α, IL-1β, IL-6, and CD-40L are proinflammatory substances activating the canonical pathway. In the canonical pathway, an inhibitor of κβ kinase (IKK) β (or IKKγ) is required for NF-κB activation. IKKβ phosphorylates Iκβ. The regulatory subunit of the IKK complex is the NF-κB essential modulator (NEMO). In the cytosol, IκB is degraded by proteasomes, and the phosphorylated heterodimer of NF-κB (p50–p65) is transferred to the nucleus and binds to the NF-κB response element. Thus, pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, iNOS, and ICAM become activated, which play role in the degradation of dopaminergic neurons (DA). In the non-canonical pathway, NEMO phosphorylates IKK-α and induces proteasomal destruction as well as proteasomal processing of p100, a subunit of the NF-B heterodimer, creating the p52-RELB active heterodimer. IKκ induces INF-α production, triggered by TLR7,9. The p52-RELB active heterodimer enters the nucleus and binds to the NF-κB response element, regulating the expression of pro-inflammatory factors. Eventually NF-κB mediated neuroinflammation plays role in Parkinson's disease through DA degradation.