The involvement of neuroinflammation and kynurenine pathway in Parkinson's disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD.

Figure 1

Basal ganglia motor circuit in Parkinson's disease: dopaminergic neurons (DA) create a direct pathway between Substantia Nigra pars compacta (SNpc) and striatum—the input nuclei of the basal ganglia. Another direct pathway connects the striatum to the internal segment of globus pallidus (GPi) and the substantia nigra pars reticulata (SNpr). GPi and SNpr are the output nuclei of the basal ganglia, which projects to the thalamus and from there to the cortex. The indirect pathway connects the striatum to output nuclei through external segment of the globus pallidus (GPe) and then subthalamic nucleus (STN). In Parkinson's disease (PD), the dopaminergic input from SNpc is progressively lost, causing a reduction in the direct pathway signal. Indirect pathway increases its activity through STN in the output nuclei and has inhibitory influence on the thalamus. It leads to a reduction of thalamic glutamateric input on the motor cortex and subsequent reduction in movement, as rigidity and bradykinesia are observed in PD patients.

Figure 2

Simplified diagram of Kynurenine pathway: during neuroinflammation, 95% of the dietary tryptophan is metabolized along the KP within the brain. The remaining 5% serves as a precursor to the synthesis of the neurotransmitter serotonin. IDO catalyses the initial and rate-limiting step in the degradation of tryptophan through KP that ultimately leads to the production of nicotinamide.

Figure 3

Activated microglial cells express IFN-γ in Parkinsonism: confocal images of the immunofluorescence of IFN-γ (red) combined with microglia cells marker—Iba-1 (green) in the SNpc of a parkinsonian monkey. Scale bar: 35 mm.

Figure 4

Model for Kynurenine pathway interactions between astrocytes, neurons, and microglia during brain inflammation. Abbreviations: TRP: tryptophan; IDO: Indoleamine 2,3-dioxygenase; KYN: kynurenine: QUIN: quinolinic acid; NMDAR: NMDA receptor; KAT: Kynurenine aminotransferase; GluT: glutamate transporter.

Figure 5

The possible role of Kynurenine pathway involvement in dopaminergic neurodegenerative process through microglia activation: Parkinson's disease is associated with chronic activation of microglia, which also can be induced by LPS or Rotenone treatments. Classic microglia activation release neurotoxic substances including reactive oxygen species (ROS) and proinflammatory cytokines as INF-γ, potent activator of Kynurenine pathway (KP). KP in activated microglia leads to upregulation of 3HK and QUIN. 3HK is toxic primarily as a result of conversion to ROS. The combined effects of ROS and NMDA receptor-mediated excitotoxicity by QUIN contribute to the dysfunction of neurons and their death. However, picolinic acid (PIC) produced through KP activation in neurons, has the ability to protect neurons against QUIN-induced neurotoxicity, being NMDA agonist. Microglia can become overactivated, by proinflammatory mediators and stimuli from dying neurons and cause perpetuating cycle of further microglia activation microgliosis. Excessive microgliosis will cause neurotoxicity to neighbouring neurons and resulting in neuronal death, contributing to progression of Parkinson's disease.