Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra and a significant reduction in dopamine levels in the striatum of the brain (Vaillancourt and Mitchell 2020), ultimately leading to the development of both non-motor and motor symptoms (Bang et al. 2021). This dopaminergic deficit is responsible for the motor symptoms observed in PD, such as resting tremors, bradykinesia (slowness of movement), rigidity, and postural instability (Moustafa et al. 2016).

Available PD treatments primarily target the modulation of dopamine signaling to alleviate motor symptoms and improve the quality of life for patients. Levodopa, the precursor of dopamine, is commonly prescribed to replenish dopamine levels in the brain, providing symptomatic relief (Ide et al. 2020). Additionally, dopamine agonists, monoamine oxidase inhibitors, and catechol-O-methyl transferase inhibitors are utilized to enhance dopaminergic activity or reduce dopamine metabolism. Despite their effectiveness in managing motor symptoms, these agents do not halt the progressive dopaminergic neurodegeneration at the core of PD. In addition, patients often experience motor fluctuations and dyskinesia as the disease progresses, which significantly challenges the management of symptoms.

Given the central role of dopaminergic neurodegeneration in PD, researchers and clinicians have sought to develop disease-modifying treatments that can decelerate or halt the process. Despite significant efforts and a better understanding of the pathogenesis of PD, the development of effective disease-modifying therapies remains challenging. Various therapeutic approaches targeting pathways involved in protein aggregation, mitochondrial function, neuroinflammation, adult neurogenesis, and neuroprotection have been explored (Lim et al. 2018; Troncoso-Escudero et al. 2018; Moon et al. 2022). Among these, emerging research has highlighted the intricate role of neuroinflammation in the pathogenesis of PD. Neuroinflammation, which involves the activation of glial cells and release of pro-inflammatory cytokines, has garnered increasing attention due to its potential contribution to neuronal damage and PD progression. With the growing recognition of the involvement of neuroinflammation in PD, the development of drugs capable of regulating neuroinflammation to manage PD has gained traction.

This review aims to provide a comprehensive overview of the role of neuroinflammation in PD pathology and highlight the importance of developing inflammation-modulating drugs to treat PD. By understanding the intricate interplay between inflammation and neurodegeneration, we can better address the unmet need for disease-modifying therapies in PD management.

Emerging evidence from studies based on animal models and humans suggests that the immune system and neuroinflammation play crucial roles in the pathogenesis of PD (Table 1). Imaging techniques, such as positron emission tomography, have enabled the visualization of neuroinflammation in patients with PD, providing valuable insights into disease progression (Bartels et al. 2010; Kang et al. 2018; Lavisse et al. 2021; Doot et al. 2022).

Table 1 . Pathological and inflammatory alterations in parkinson’s disease.

		Group	Regulation in PD	References
PD patients		PD (n = 5), DAT (n = 9), cerebro vascular accidents (n = 2), without premortem neurologic disease (n = 7)	↑ Lewy bodies in SN of PD patients ↑ GFAP+, HLA-DR+ cells in SN of PD patients	McGeer et al. (1988)
		De novo PD (n = 22), sporadic AD (n = 11)	↑ IL-6 and IL-1β in CSF of PD patients	Blum-Degen et al. (1995)
		Healthy participants (n = 22), early-stage PD (n = 24)	↑ Th1/total T cells, IL-10, IL-17A in blood of PD patients	Liu et al. (2022)
		LRRK2-G2019S-PD patients (n = 33), idiopathic PD patients (n = 33)	↑ Rest tremor, postural instability, freezing of gait, dyskinesias, UPSIT score, depression and bristol scale in LRRK2-G2019S PD patients ↓ Hyposmia and action tremor in LRRK2-G2019S PD patients	Gaig et al. (2014)
		PD (n = 4)	↑ CD68 in olfactory bulb of PD patients	Vroon et al. (2007)
PD animal models	Neurotoxin	LPS rats (10 μg/4 μL, 2 days and 4 weeks)	↑ iNOS, TNF-α and IL-6 in SN of LPS administrated rats ↑ α-syn in SN of LPS administrated rats	Choi et al. (2010)
		LPS mice (5 μg/1 μL, stereotaxic)	↓ TH+ neurons in SN of LPS administrated WT mice ↑ Isolectin B4 and LRRK2 in SN of LPS administrated WT mice ↑ TH+ neurons in SN of LPS administrated LRRK2−/− mice ↓ Isolectin B4 and LRRK2 in SN of LPS administrated LRRK2−/− mice	Moehle et al. (2012)
		MPTP mice (20 mg/kg, i.p., 4 times at 2 h intervals, 1, 3 and 5 days)	↑ IL-1β, IL-1α and IL-1ra in SN, striatum and olfactory bulb of MPTP administrated mice	Vroon et al. (2007)
		Adβgal (stereotaxic, 7, 21, 40, 60 days)	↓ TH+ neurons in SN of Adβgal administrated rats ↑ IL-1β, GFAP and CD68 in SN of Adβgal administrated rats	Ferrari et al. (2006)
		MACO rats	↑ DJ-1 in brain of cerebral I/R injury rats ↑ TNF-α, IL-1β and IL-6 in brain of cerebral I/R injury rats	Peng et al. (2020)
		NLRP3A350V mice, Parkinflx/flx mice, Casp1+/−/parkin+/flx mice (adged 8-10 weeks)	↑ NLRP3, cleaved caspase 1 and Iba-1 in SNpc of AAV GFP-Cre injected Parkinflx/flx mice and NLRP3A350V mice ↓ TH+ neurons in SNpc of Parkinflx/flx mice and NLRP3A350V mice	Panicker et al. (2022)
	Transgenic	Nlrp3−/−, Cx3CrlCreER, Nlrp3D301NneoR mice (aged 9-12 weeks)	↓ Motor function in MPTP administrated Nlrp3+/+ mice ↓ TH+ neurons and dopamine in SN of MPTP administrated Nlrp3+/+ mice ↑ Iba-1, IL-1β and ASC in SN of MPTP administrated Nlrp3+/+ mice	Lee et al. (2019)
		LRRK2G2019S, LRRK2−/− mice	↑ LRRK2 in brain of human α-syn fibrils administrated mice	Xu et al. (2022)
		Parkin−/−, PINK1−/− mice	↑ IL-12 and IL-13 in serum of Parkin−/− and PINK1−/− mice ↑ CXCL1, CCL2 and CCL4 in serum of Parkin−/− and PINK1−/− mice	Sliter et al. (2018)
		DJ-1-deficient mice (Park7−/−)	↓ TNF-α, IL-1β and IL-23p19 in striatum of Park7−/− mice	Nakamura et al. (2021)
		t-SCI rats	↑ DJ-1 in t-SCI in brain of rats ↑ NLRP3, cleaved caspase 1, IL-1β, IL-18 and MMP9 in t-SCI in brain of rats	Cai et al. (2022)

This table provides an overview of pathological features and inflammatory alterations in both PD patients and animal models. For details and references, see main text. ASC, apoptosis-associated speck like protein containing a CARD; AD, Alzheimer’s disease; CCL, chemokine (C-C motif) ligand; CD68, cluster of differentiation; COX-2, cyclooxygenase 2; CSF, cerebrospinal fluid; CXCL1, chemokine (C-X-C motif) ligand 1; DAT, dopamine transporter; GFAP, glial fibrillary acidic protein; HLA-DR, human leukocyte antigen-DR; IL, interleukin; iNOS, inducible nitric oxide synthase; I/R, ischemia/reperfusion; LPS, lipopolysaccharide; LRRK2, leucine rich repeat kinase 2; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MMP9, matrix metallopeptidase 9; NLRP3, nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain containing 3; PBMC, peripheral blood mononuclear cells; PD, Parkinson’s disease; SN, substantia nigra; TH, tyrosine hydroxylase; Th1, type 1 T helper; TNF, tumor necrosis factor; t-SCI, traumatic spinal cord injury; UPSIT, University of Pennsylvania smell identification test; WT, wild type..

Microglia are specialized immune cells found within the central nervous system (CNS) and are considered the main form of active immune defense in the CNS (Filiano et al. 2015). Their ability to recognize certain patterns, through receptors known as pattern-recognition receptors, enables them to detect molecules linked to pathogens and damage, leading to microglial stimulation (Akira et al. 2006). Microgliosis, the continuous activation of microglia with a pro-inflammatory nature, has been identified as a contributing factor in various neurodegenerative diseases, including PD. Early evidence has shown that people diagnosed with both PD and PD combined with dementia exhibit a high concentration of activated microglia in their substantia nigra (McGeer et al. 1988). The activation of microglia, astrogliosis, and the infiltration of activated immune cells from the periphery contribute to harmful changes in the brain, resulting in neuronal death and the advancement of PD (Hirsch and Hunot 2009). Additionally, the number of microglia and their activation state correlate with α-synuclein deposition in the pathway involved in dopaminergic neuron loss (Croisier et al. 2005; Choi et al. 2010). Moreover, inflammatory cytokines like interleukin-1beta (IL-1β) and IL-6, which are released upon microglial activation, have been identified in the nigrostriatal pathway of brains affected by PD in both humans and corresponding animal models (Ferrari et al. 2006). These mediators exacerbate dopamine impairment and even lead to neuronal death (Blum-Degen et al. 1995; Vroon et al. 2007). In addition, according to recent research, early stages of PD are associated with microglial activation in the putamen and peripheral T helper 1 phenotypic bias (Liu et al. 2022). Consequently, peripheral adaptive immunity may indirectly result in microglial activation in the neurodegenerative process involved in PD (Liu et al. 2022).

The NOD-, LRR- and pyrin domain containing 3 (NLRP3) inflammasome is emerging as a pivotal component in understanding the neuroinflammatory processes involved in PD. This intracellular multiprotein complex, primarily known for its role in initiating innate immune responses, has recently been connected to the intricate mechanisms underlying PD pathogenesis. Upon activation, NLRP3 leads to the cleavage of pro-caspase-1 into active caspase-1, thereby enabling the conversion of pro-IL-1β into their active form (Franchi et al. 2009). These pro-inflammatory cytokines contribute to a chronic inflammatory state within the brain. This phenomenon activates the NLRP3 inflammasome and may also further exacerbate neuroinflammatory responses, establishing a feedback loop that sustains microgliosis (Heneka et al. 2018). Furthermore, dysregulation of the NLRP3 inflammasome has been linked to dopaminergic neuronal loss, a defining pathological hallmark of PD (Lee et al. 2019; Panicker et al. 2022). Some preclinical trials investigating the use of NLRP3 inhibitors to attenuate neuroinflammation and ameliorate neurodegenerative symptoms have yielded promising results (Coll et al. 2015; Lonnemann et al. 2020; Xue et al. 2021; Zeng et al. 2021). These associations emphasize the potential of NLRP3 as a therapeutic target.

Several studies have reported a unique link between certain genes associated with PD and the immune response of CNS cells. The leucine-rich repeat kinase 2 (LRRK2) gene has emerged as a pivotal component in PD; not only is it one of the most commonly mutated genes in familial PD, but variations in LRRK2 are also linked with sporadic PD cases (Zimprich et al. 2004; Gaig et al. 2014; Cookson 2017). LRRK2 encodes a protein kinase that is involved in a multitude of cellular processes, including autophagy, vesicle trafficking, and immune response. In PD, LRRK2 mutations lead to an aberrant activation of microglial cells. Reducing LRRK2 levels through knockdown or inhibiting its kinase activity in primary microglia leads to a decrease in the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-1β (Moehle et al. 2012; Russo et al. 2015). Moreover, mutated LRRK2 may enhance α-synuclein pathology, further exacerbating the inflammatory response (Bieri et al. 2019; Xu et al. 2022). The Phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene has been identified as a critical component in the development and progression of PD, specifically in connection with neuroinflammation. In healthy neurons, PINK1 monitors mitochondrial health and when damage occurs, it triggers mitophagy, the process involved in the selective degradation of damaged mitochondria. Mutations in the PINK1 gene can disrupt this protective mechanism, leading to an accumulation of damaged mitochondria within the cell. Mitochondrial accumulation can trigger a cascade of pro-inflammatory signals, inducing microglial activation, and the release of inflammatory mediators such as TNFα and IL-1β (Sliter et al. 2018). The activated microglia, in turn, can cause further damage to the neurons, creating a vicious cycle of neuroinflammation that results in the neurodegenerative process observed in PD. PINK1 has also been associated with immune responses outside the CNS, like alterations in the peripheral immune cells of patients with PD with PINK1 mutations, indicating a broader systemic involvement in inflammatory regulation (Zhou et al. 2019a). The DJ-1 gene (Parkinson disease protein 7, PARK7), associated with PD, is primarily expressed in astrocytes and microglia, and it has been investigated for its potential link to inflammation. In the context of ischemic stroke, DJ-1 has been shown to have anti-inflammatory properties by suppressing the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-18 (Peng et al. 2020; Nakamura et al. 2021). Moreover, recent research has indicated that DJ-1 reduces neuroinflammation and the associated impairment of the blood-spinal cord barrier by inhibiting the activation of the NLRP3 inflammasome through the suppressor of cytokine signaling 1/Ras-related C3 botulinum toxin substrate 1/reactive oxygen species signaling pathway in a rat model of traumatic spinal cord injury (Cai et al. 2022).

DPP-4 is a serine exopeptidase involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. DPP-4 is widely distributed in several organs, including the liver, lungs, intestinal epithelium, placenta, kidney, renal proximal tubules, and neurons, as well as in body fluids including the cerebrospinal fluid (Green et al. 2006; Kosaraju et al. 2013). In addition to its crucial role in the regulation of blood glucose levels, which are commonly used in the treatment of type 2 diabetes mellitus (T2DM), DPP-4 can be directly associated with the modulation of various non-incretin related processes, including inflammatory responses and neurophysiological functions (Aertgeerts et al. 2004).

Several reports have demonstrated that DPP-4 inhibitors modulate the activation of immune cells in adipose tissues (Shirakawa et al. 2011), and the inhibition of DPP-4 activity reduces the expression and activity of the macrophage marker F4/80 (Klein et al. 2014). The DPP-4 inhibitors, sitagliptin and NVPDPP728, exhibit significant potential in repressing the expression of NLRP3 and IL-1β in human macrophages (Dai et al. 2014). In patients with T2DM, a meta-analysis by Xie et al. confirmed that DPP-4 inhibitors exhibit substantial anti-inflammatory effects. The study, encompassing 22 trials with 1595 patients with T2DM, revealed that DPP-4 inhibitor therapy is notably linked to reductions in C-reactive protein, TNF-α, IL-6, and IL-1β levels (Xie et al. 2023). Sitagliptin is a DPP-4 inhibitor with anti-inflammatory and antioxidant properties, and effectively alleviates intestinal inflammation associated with severe acute pancreatitis (SAP), both in vitro and in vivo. Sitagliptin treatment leads to the upregulation of nuclear factor erythroid-derived 2-like 2 (Nrf2) expression while concurrently downregulating NF-κB expression in mice with SAP, thereby contributing significantly to its therapeutic efficacy (Zhou et al. 2019b). Moreover, for severe acute pancreatitis-related acute lung injury, sitagliptin is a promising therapeutic agent that activates the p62-kelch like ECH associated protein 1-Nrf2 signaling pathway, leading to Nrf2 nuclear translocation (Kong et al. 2021). Vildagliptin effectively suppresses the generation of reactive oxygen species (ROS), the production of vascular inflammatory factors, and monocyte adhesion to endothelial cells, potentially through the inhibition of toll-like receptor 4 and NF-κB nuclear signals (Wiciński et al. 2020).

It is not yet certain whether the anti-inflammatory effects of DPP4 inhibitors are mediated through the accumulation of GLP1 or if they are independent of GLP1 receptor activation and instead directly related to the inhibition of DPP4 activity.

Lots of studies have demonstrated that the anti-inflammatory potential of DPP-4 inhibitors could be associated with the accumulation of GLP-1 and GLP-2, the two main targets of DPP-4; GLP-1 and GLP-2 activate their receptors and increase intracellular cyclic adenosine monophosphate, which activates their downstream pathways involved in the inhibition of the neuroinflammatory response (Flock et al. 2007). Linagliptin has been implicated in mitigating Aβ-induced neurotoxicity through GLP-1-mediated pathways, evidenced by the upregulation of insulin and insulin-like growth factor-1 (IGF-1) gene expression (Sedighi et al. 2021). Ide et al. found that linagliptin improved cognitive impairment in streptozotocin-induced diabetic mice by reducing proinflammatory cytokines, as well as inhibiting microglial activation. These effects were observed independently of glucose-lowering, suggesting a direct neuroprotective effect of linagliptin beyond its antidiabetic properties. This neuroprotective effect occurs independently of changes in blood glucose levels, suggesting a GLP-1-mediated mechanism. Additionally, in a rotenone-induced rat model of PD, linagliptin treatment increased striatal dopamine and active GLP-1 levels in the brain, indicating GLP-1’s involvement in its neuroprotective effects. Moreover, linagliptin attenuated rotenone-induced alterations in inflammatory markers like TNF-α. These findings underscore the potential of linagliptin’s anti-inflammatory and neuroprotective actions mediated through GLP-1-dependent mechanisms.

On the other hand, there are evidences indicating that changes in the activity of DPP4 itself are associated with inflammatory responses, suggesting that the anti-inflammatory activity of DPP4 inhibitors could occur independently of GLP1 accumulation. In facts, DPP-4 expression is altered in inflammation and/or immunity-associated diseases and acts as a regulator of immune cells (Trzaskalski et al. 2020). DPP-4 is involved in the maturation and phenotypic differentiation of T-cells, and therefore, in immune regulation (Al-Badri et al. 2018). Ghorpade et al. (2018) demonstrated the interaction between the liver and visceral adipose tissues (VAT), wherein obesity triggers hepatocytes to produce DPP-4, contributing to inflammation in adipose tissue macrophages (ATMs). In obese mice, DPP-4 synthesis by hepatocytes, along with the plasma factor Xa, triggers inflammation in visceral ATMs. Moreover, silencing DPP-4 expression in hepatocytes alleviates VAT inflammation and insulin resistance (Ghorpade et al. 2018). Renal protection has been a focal point of DPP-4 inhibitor studies, revealing pathways independent of GLP-1. Notably, DPP-4 inhibitors such as linagliptin and vildagliptin have demonstrated renoprotective effects mediated by substrates beyond GLP-1 (Kanasaki et al. 2014; Shi et al. 2016). These include the upregulation of Stromal Cell-Derived Factor-1 (SDF-1), modulation of microRNAs (miR-29 and miR-200a), and downregulation of Transforming Growth Factor-β (TGF-β) signaling. It should be noted that while several studies have highlighted the anti-inflammatory effects of DPP-4 inhibitors in neurodegenerative diseases, there remains a lack of conclusive evidence regarding their actions through GLP-1 independent pathways. In conjunction with these findings, reports on the anti-inflammatory effects of DPP4 inhibitors in the brain suggest that the anti-inflammatory effects of DPP4 inhibitors in neuroinflammatory lesions may be attributable not only to GLP1 accumulation but also to the inhibition of DPP4 enzyme activity itself. However, further research is needed to elucidate the underlying mechanisms by which DPP4 enzyme activity inhibition specifically contributes to the regulation of inflammatory responses.

Multiple in vitro studies have demonstrated that DPP-4 inhibitors exhibit a neuroprotective effect on neuronal cells (Abdelsalam and Safar 2015; Wiciński et al. 2018; Zhang et al. 2020). When exposed to neurotoxic stimuli, such as oxidative stress, inflammation, or excitotoxicity, neuronal cells treated with DPP-4 inhibitors exhibited enhanced viability compared to untreated cells. This finding suggests a potential role for DPP-4 inhibitors in preserving neuronal health and countering neurodegenerative processes. The experimental findings indicating the neuroprotective of DPP-4 inhibitors in various neuronal cell damage models, including those related to neurodegenerative diseases, have been emphasized (Table 2). Both in vitro and in vivo studies using animal models have revealed that DPP-4 inhibitors possess antioxidant properties and can mitigate oxidative damage in neurons. DPP-4 inhibitors can protect neurons from oxidative injury by scavenging free radicals and enhancing endogenous antioxidant defenses, potentially slowing the progression of neurodegenerative disorders. Several preclinical studies employing animal models of cognitive impairment have shown that DPP-4 inhibitors can ameliorate cognitive deficits. These improvements in cognitive function are associated with increased synaptic plasticity, enhanced neurogenesis, and improved cerebral blood flow. Moreover, Sitagliptin was found to improve memory deficits in PD rats by upregulating brain-derived neurotrophic factor to prevent neuronal and dendritic spine loss (Li et al. 2018). All these findings suggest that DPP-4 inhibitors might attenuate the cognitive decline observed in neurodegenerative diseases.

Table 2 . Neuroprotective effects of DPP-4 inhibitors.

Drug	Model	Effects		References
		Pathological changes	MOA
Linagliptin	SH-SY5Y cells treated Aβ1-42	↑ Cell viability	↓ Inflammation; ↓ TNF-α, IL-1β and IL-6, ↑ Wnt1, pCREB, and PKCε	Sedighi et al. (2021)
	Rotenone mice (1.5 mg/kg, s.c., 21 days)	↑ Locomotor activity ↑ DA level in striatum	↓ Oxidative stress; ↑ SOD, catalase and GSH in brain homogenate ↓ Inflammation; ↓ TNF-α level in brain homogenate	Abhangi and Patel (2022)
	Rotenone rats (2 mg/kg, s.c., 28 days)	↑ Locomotor activity ↓ Catalepsy	↓ Inflammation; ↓ TNF-α, IL-6, and HIF1-α, ↑ DJ-1 in the midbrain and striatum ↓ Apoptosis; ↓ caspase-3 in the midbrain and striatum	ElGamal et al. (2023)
	Focal Ischemic Stroke in Hyperglycemic mice	↓ Neuronal cell death ↑ Locomotor Activity	↓ Inflammation; ↓ Iba-1, IL-1β and IL-6 ↓ Apoptosis; ↓ caspase-3 and Bcl-2, ↑ p-Akt, p-mTOR, and Bax	Zhang et al. (2020)
	HFD TauP301S mice PS19 transgenic mice	↑ Cognitive function No significant correlation in phosphorylated tau in hippocampus		Nakaoku et al. (2019)
Vildagliptin	MPTP mice (30 mg/kg, i.p., 14 days)	↑ Locomotor activity ↑ TH+ neurons in SNpc ↑ TH density in striatum	↓ Apoptosis; ↓ caspase-3 and Bax/Bcl-2 ratio, ↓ p-ERK/ERK and p-JNK/JNK in striatum Autophagy; No significant in LC3B and LC3B-II in striatum and SNpc	Pariyar et al. (2022)
	SH-SY5Y cells treated MPP+	↑ Cell viability	↓ Apoptosis; ↑ p-Akt/Akt, ↓ p-ERK/ERK and p-JNK/JNK ↓ Autophagy; ↓ LC3B-II
	Rotenone rats (1.5 mg/kg, s.c., 21 days)	↑ Locomotor activity ↑ DA in striatum ↓ Body weight loss	↓ Inflammation; ↓ MPO, ICAM, TNF-α and iNOS in striatum ↓ Apoptosis; ↓ caspase-3, cytochrome c, TBARS and Nrf2 in striatum	Abdelsalam and Safar (2015)
	AlCl3 rats (100 mg/kg, oral, 60 days)	↑ Locomotor activity ↑ Cognitive function ↓ Aβ1-42 in hippocampus	↓ Oxidative stress; ↓ FOXO1 in hippocampus ↓ Inflammation; ↓ TNF-α in hippocampus ↓ Apoptosis; ↓ Bax and caspase-3, ↑ Bcl-2 in hippocampus ↑ Klotho, p-AKT and p-ERK, ↓ STAT3 and JAK2 in hippocampus	Yossef et al. (2020)
Alogliptin	Rotenone rats (1.5 mg/kg, i.p., 21 days)	↑ Locomotor activity ↑ TH density in SNpc	↓ Inflammasome; ↓ Iba-1, caspase-1, TLR-4, NLRP3, HMGB1 and IL-1β in striatum	Safar et al. (2021)
Saxagliptin	STZ-induced AD rats (3 mg/kg, ICV, 3 days)	↑ Cognitive function ↓ Aβ1-42 levels in hippocampus ↓ Total tau levels in hippocampus	↓ Inflammation; ↓ TNF-α and IL-1β in hippocampus	Kosaraju et al. (2013)
	Aβ-induced AD rats (300 pmol/day, stereotaxic, 15 days)	↑ Cognitive function	↓ Oxidative stress; ↓ MDA, ↑ SOD, catalase, GSH, Nrf2 and HO-1	Li et al. (2018)
Omarigliptin	LPS rats (250 μg/kg, i.p., 7 days)	No significant in locomotor activity ↑ Cognitive function	↓ Oxidative stress; ↑ Nrf2 and HO-1 in hippocampus ↓ Inflammation; ↓ TNF-α, IL-8, TGF-β1, TLR-4 and NLRP3, ↑ IL-10 in hippocampus ↑ Autophagy; ↓ p-AKT and GSK-3β, ↑ beclin-1 in hippocampus	Kabel et al. (2022)
Sitagliptin	Rotenone rats (3 mg/kg,s.c., 10 days)	↑ Locomotor activity ↑ TH+ neurons in SNpc ↑ DA level in striatum	↓ Apoptosis; ↓ Bax, ↑ Bcl-2 in SN ↑ GDNF level in SN ↓ Inflammation; ↓TGF-β1, IL-1β and IL-6 in SN	Badawi et al. (2017)
	6-OHDA rats (8 μg/rat, stereotaxic)	↑ Cognitive function ↑ TH levels in SN ↑ Spine density in hippocampal CA1	↑ BDNF level in brain	Li et al. (2018)

This table provides an overview of the neuroprotective effects of DPP-4 inhibitors with underlying pathological and mechanical changes in PD in both animal cell lines models. For details and references, see main text. AD, Alzheimer’s disease; Aβ, amyloid β; Bcl-2, B cell lymphoma 2; CA1, cornu ammonis; CREB, cAMP-response element binding protein; DA, dopamine; ERK, extracellular signal-regulated kinase; FOXO1, forkhead box protein O1; GSH, glutathione; GSK-3β, glycogen synthase kinase 3 beta; HIF1-α, hypoxia-inducible factor 1-alpha; HFD, high fat diet; HMGB1, high-mobility group box 1; HO-1, heme oxygenase-1; Iba-1, ionized calcium-binding adapter molecule-1; ICAM, intercellular adhesion molecule-1; ICV, intracerebroventricular; IL-1β, interleukin-1β; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; JAK2, Janus kinase; JNK, c-Jun N-terminal kinase; LC3B, microtubule-associated protein 1A/1B-light chain 3B; LPS, lipopolysaccharide; MDA, malondialdehyde; MPO, Myeloperoxidase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NLRP3, nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; Nrf2, Nuclear factor erythroid-2-related factor 2; PKCε, protein kinase C; mTOR, mammalian target of rapamycin; SN, substantia nigra; SNpc, substantia nigra pars compacta; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription; STZ, streptozotocin; TBARS, thiobarbituric acid reactive substances; TGF-β1, transforming growth factor-β1; TH, tyrosine hydroxylase; TLR-4, toll-like receptor-4; TNF-a, tumor necrosis factor-α..

In several experimental studies using animal models, DPP-4 inhibitors have been shown to reduce neuroinflammation by suppressing microglial activation and inhibiting the production of pro-inflammatory cytokines in the brain. Accumulated evidence has revealed that DPP-4 inhibitors suppress neuroinflammation by reducing TNF-α and IL-1β levels, thereby contributing to the amelioration of the pathology associated with several neurodegenerative diseases. Exendin-4 and linagliptin treatments have induced microglial polarization in the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model (Yu et al. 2023). Pretreatment with linagliptin also attenuates amyloid-β (Aβ)-induced inflammation and cytotoxicity by suppressing the release of IL-6 in human SH-SY5Y neuroblastoma cells exposed to Aβ cytotoxicity (Sedighi et al. 2021). Linagliptin dose-dependently improved cognitive impairment and reduced the levels of soluble Aβ (1-42), TNF-α, IL-1β, IL-6, acetylcholinesterase, and oxidative/nitrosative stress markers in a rat model of Alzheimer’s disease induced by intracerebroventricular streptozotocin treatment (Siddiqui et al. 2023). Vildagliptin effectively improves motor performance, reduces striatal dopamine depletion, and suppresses inflammatory mediators like NF-κB and TNF-α in a rat model of rotenone-induced PD (Abdelsalam and Safar 2015). Sitagliptin also reversed nigrostriatal degeneration, improved motor performance, and decreased the levels of IL-1β, IL-6, and TGF-β1 in the rat brain in a rotenone-induced model of PD (Badawi et al. 2017). Sitagliptin, both alone and in combination with pregabalin, alleviates acute epileptogenesis induced by pentylenetetrazole in mice. The findings demonstrated that sitagliptin exerted substantial anti-inflammatory effects by modulating the levels of inflammatory factors like Nrf2 and NF-κb (Nader et al. 2018). Omarigliptin exhibits anti-inflammatory effects by inhibiting NF-κB activation, leading to a reduction in nitric oxide (NO) production and the expression of inducible NO synthase (iNOS) in a model of neurotoxin-induced toxicity in PC12 cells, which mimics PD (Gouda and Cho 2022).

Preclinical studies have shown that DPP-4 inhibitors may protect dopaminergic neurons from degeneration, enhance neuroplasticity, and attenuate neuroinflammation (Table 2). These findings have sparked interest in exploring the therapeutic potential of DPP-4 inhibitors in PD, focusing on dopaminergic neuron degeneration.

Numerous clinical trials have assessed the neurorestorative potential of antidiabetic drugs in preclinical models of PD, yielding positive outcomes. The most extensively reported potential for repurposing antidiabetic drugs as treatment for PD lies in GLP1 receptor agonists. Specifically, clinical trial (NCT01971242) (University College London, 2016) are underway for exenatide, a GLP-1 receptor agonist, as a treatment for PD. These clinical trials have evaluated the impact of exenatide in patients with PD, utilizing a randomized, double-blind, and placebo-controlled design, wherein participants received weekly subcutaneous injections of either exenatide or a placebo alongside their standard PD treatment (Athauda et al. 2017). The outcomes of these trials provided insights into whether the neuroprotective effects of exenatide, previously observed in preclinical models, could translate into positive outcomes in a clinical setting (Athauda et al. 2017). The therapeutic potential of GLP-1 agonist lixisenatide in PD has also garnered significant interest following promising results from clinical trials (NCT03439943) (University College London, 2023). Participants receiving lixisenatide showed less disability, as assessed by the Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS), compared to those receiving placebo. Importantly, improvements in the MDS-UPDRS scores were observed in both ON and OFF states, indicating a potential disease-modifying effect of lixisenatide beyond the amplification of pharmacological impacts of existing medications. Lin et al. reported that diabetic patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, particularly vildagliptin, exhibited a significantly lower risk of PD compared to those using other oral antidiabetic drugs (Lin et al. 2023). Additionally, Jeong et al. demonstrated that treatment with DPP-4 inhibitors in diabetic patients with PD was associated with higher baseline nigrostriatal dopamine transporter availability and slower longitudinal increase in levodopa-equivalent dose, suggesting potential beneficial effects on motor outcomes in this population (Jeong et al. 2021). Furthermore, given that DPP-4 inhibitors are small molecules, they are more practical for use in patients with PD compared to larger peptide-based molecules like GLP-1 receptor agonists. Despite their mechanism primarily involving the augmentation of GLP-1 signaling, which may confer anti-inflammatory effects, the inhibition of DPP-4 itself could also contribute to additional anti-inflammatory effects. This dual mechanism suggests that the use of DPP-4 inhibitors in PD patients may offer comprehensive neuroprotective effects.

In summary, the current state of therapeutics for PD highlights a significant demand for innovative disease-modifying treatments. This review discusses the current understanding of the anti-inflammatory properties of DPP-4 inhibitors and their potential as a novel therapeutic strategy for PD (Fig. 1). Elucidating the mechanisms through which DPP-4 inhibitors influence neuroinflammation may offer new prospects for disease-modifying therapies in PD. However, it is crucial to conduct further research, including clinical trials, to confirm the validity of the preclinical findings discussed in this review and ascertain the safety and effectiveness of DPP-4 inhibitors in treating PD.

Figure 1. Role of DPP4 inhibitors in neuroinflammation.

The authors declare that they have no conflict of interest.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1A2C1013180, RS-2023-00246151).