Parkinson's disease (PD), initially coined as “Shaking Palsy” by James Parkinson in 1817, stands as the second most common neurodegenerative disorder, impacting over 4 million individuals across the globe today. The prevalence of PD escalates with age, notably affecting around 3% of the population over 80 years (Van Den Eeden et al., 2003). Beyond the established risk factor of aging, the pathophysiological development of the disease is influenced significantly by a blend of environmental, idiopathic, and genetic factors (Liu et al., 2003; Tysnes and Storstein, 2017). Remarkably, <10% of the PD cases can be attributed to a familial origin, with the vast majority classified as idiopathic, primarily linked to environmental factors.

PD is recognized for its key motor symptoms - bradykinesia, rigidity, rest tremor and postural instability – arising due to insufficient dopamine in the basal ganglia. Motor symptoms typically emerge after around 30% of dopaminergic neurons in the pars compacta of substantia nigra (SNpc) are lost (Grosch et al., 2016). Interestingly, various non-motor aspects like olfactory and cognitive dysfunction, depression, sleep disorders, autonomic dysfunction (urinary incontinence, constipation, postural hypotension, etc.), cardiac sympathetic denervation, pain, and fatigue manifest in the early PD stages, often preceding motor symptoms by over a decade (Kalia and Lang, 2015; Khoo et al., 2013). As PD advances, standard symptomatic treatments become less effective in managing deteriorating motor symptoms, and prolonged dopaminergic therapy leads to motor and non-motor fluctuations, drug-induced dyskinesia, psychosis (Hely et al., 2005). In later PD stages, inadequate control of motor and non-motor symptoms, along with treatment-related complications significantly complicate patient care.

The central pathology of PD involves the progressive loss of dopaminergic neurons within the SNpc and the presence of Lewy bodies - intraneuronal inclusion bodies composed of aggregated misfolded α-synuclein polymers, ubiquitin, complement, and structural cytoplasmic proteins (Moore et al., 2005; Phani et al., 2012). These pathological aggregates are distributed throughout various brain and body regions, including SNpc, cerebral cortex, adrenal medulla, cutaneous nerves, salivary glands, cardiac plexus, dorsal nucleus of the vagus nerve, sympathetic ganglia, and myenteric plexus of the gut (Bhattacharjee et al., 2019; Cardinale et al., 2021). In fact, the hypothesis regarding Lewy pathology suggests its initiation in the peripheral system before its spreading to the central nervous system (CNS) (Braak et al., 2003). Nevertheless, early in the premotor phase of PD, the toxic accumulation of α-synuclein polymers within presynaptic terminals disrupts neurotransmitter release before occurrence neuronal degeneration occurs (Cardinale et al., 2021). This underscores PD as a multifactorial and systemic neurodegenerative disorder.

While the abovementioned histopathological changes in PD are well-established, the precise pathophysiological mechanisms underlying these changes remain incompletely understood. However, emerging evidence from neuropathological and biochemical studies on PD brains suggests a role for neuroinflammation in its pathogenesis. These studies underline mitochondrial dysfunction and highlight the involvement of both innate and adaptive immune system mediators in disease progression. This included the uncontrolled activation of microglia, release of proinflammatory cytokines, nitric oxide, prostaglandin E2, reactive oxygen and nitrogen species, as well as increased autoreactive T lymphocytes in the peripheral nervous system and augmented antigen-presenting cells and MHC II complexes in the peripheral and CNS (More et al., 2013). Viral infections have also been linked to dopaminergic neuron degeneration (Caggiu et al., 2016, Caggiu et al., 2017; Scheperjans et al., 2015).

This comprehensive review delves deeply into the intricate role and profound impact of inflammatory pathways in the development and progression of PD, shedding light on the complex mechanisms at play.