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International Journal of Pharmaceutical InvestigationNOW IN
Review

Exploring Novel Emerging Therapeutic Strategies for Parkinson’s Disease: A Narrative Review

Vishal Kulkarni1, R T Sai Kumari2, Sanjunath Satteppa Muchandi3, Sanatkumar Bharamu Nyamagoud4★, H M Nanjappaiah5, Vishwanath Jagadevappa Hooli6, Sangamesh Sharanbasappa Tadkal7, Prasad Nijaguni Bali8★ Corresponding author

  1. 1Department of Medical Oncology, Karnataka Medical College and Research Institute, Hubballi, Karnataka, INDIA.
  2. 2Consultant Radiation Oncologist, Karnataka Cancer Therapy and Research Centre, Navanagar, Hubballi, Karnataka, INDIA.
  3. 3Formulation Development (Pharma), Himalaya Wellness Company, Makali, Bengaluru, Karnataka, INDIA.
  4. 4Department of Pharmacy Practice, SDM Trust’s Danigond College of Pharmacy, Terdal, Karnataka, INDIA.
  5. 5Department of Pharmacology, BLDEA’s SSM College of Pharmacy and Research Centre, BLDE University Campus, Vijayapura, Karnataka, INDIA.
  6. 6Department of Pharmacognosy, HKE’s Institute of Pharmacy, Kalaburagi, Karnataka, INDIA.
  7. 7Department of Pharmacy Practice, Shetty Institute of Pharmaceutical Sciences, Kalaburagi, Karnataka, INDIA.
  8. 8Department of Pharmacy Practice, HKE’s Matoshree Taradevi Rampure Institute of Pharmaceutical Sciences, Kalaburagi, Karnataka, INDIA.

CORRESPONDENCE

Sanatkumar Bharamu Nyamagoud

Associate Professor and Head, Department of Pharmacy Practice, SDM Trust’s Danigond College of Pharmacy, Terdal-587315, Karnataka, INDIA.

dr.sanathnyamagoud@gmail.com

Received: 28-01-2026; Revised: 02-03-2026; Accepted: 11-05-2026.

Volume 16, Issue 3 · pp. 880–884 · PUBLISHED Jul-Sep 2026 · DOI: 10.5530/ijpi.20261067

View on IJPI original site ↗

ABSTRACT

Parkinson's Disease (PD) is a common neurodegenerative disorder. It is defined by a progressive loss of dopamine neurons in the substantia nigra pars compacta and neurodegeneration, which eventually results in a decrease in dopamine levels. This review provides an overview of PD. Parkinson's disease patients exhibit both non-motor symptoms like depression and anxiety as well as motor symptoms including bradykinesia, tremor and rigidity. PD involves Lewy body formation, dopamine neuron death and molecular pathways with α-synuclein clumping. Current PD management focuses on relieving motor symptoms through dopamine medications, glutamate­blocking and surgery. However, non-motor symptoms re­quire additional medications. This literature review also explores innovative treatment approaches like Aiming for α-Syn Aggregation, enhancing autophagy and promoting neuroprotection. It stops bad proteins from forming, blocks harmful genes and boosts the body's cleaning systems. There's also a focus on creating treatments that protect nerve cells. Some are channel blockers; others encourage cell response. Iron binders are used too. Inflammation in the brain is another focus. This is done through enzyme control and tweaking certain cell responses.

KEYWORDS

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FULL TEXT

INTRODUCTION

Approximately 1% of those over 60 suffer with Parkinson's Disease (PD) and it is the second most prevalent neurological condition worldwide. Men are more likely than women to have Parkinson's Disease (PD) at a prevalence rate of 1.6:1. Bradykinesia, stiffness, postural instability and resting tremor are the main clinical indicators of PD. Dopamine (DA) insufficiency in the striatum, resulting from the progressive death of dopaminergic neurons in the substantia nigra pars compacta is the primary source of these symptoms (Dong et al., 2016). Other symptoms include difficulty sleeping, mental health issues and issues with the bladder and digestive system. Parkinson's disease can have various causes, including heredity, environment, malnourishment, age of growth, gender and brain injury. Many proteins and molecular pathways are connected to the genesis of Parkinson's disease. Alpha-Synuclein (α-Syn) and other misfolded or abnormal proteins accumulate and deposit, signaling or actually causing dying DA neurons (Gouda et al., 2022). Some Parkinson's Disease (PD) instances have been connected to genes like Daisuke-Junko-1, phosphatase, Ubiquitin C-terminal Hydrolase L1 (UCHL1), Glucocerebrosidase (GBA1) and Tensin homolog (PTEN)-Induced Kinase 1 (PINK1) among others (Cacabelos, 2017).

Innovative Treatment Approaches for Parkinson's Disease

Aiming for α-Syn Aggregation

Misfolding Inhibitors of α-Syn

Finding efficient methods to inhibit the α-Syn aggregation process has been difficult because it is an intricate procedure that is dependent on external factors (Pfeiffer, 2016). However, in order to preserve cellular proteostasis under stressful situations, a number of Heat Shock Proteins (HSPs), in particular HSP70 and HSP104, helped to ATP-independently partially stabilize the transitory folding intermediates. This enabled them to stop α-Syn aggregation in both in vivo and in vitro settings (Gorenberg and Chandra, 2017). Moreover, curcumin, a spice and other naturally occurring α-Syn aggregation inhibitors have a strong neuroprotective effect (Nebrisi, 2021). Nowadays, a lot of focus is placed on the study of small-molecule α-Syn inhibitors. NPT088 and NPT200-11 are two exceptional candidates that are presently undergoing clinical studies. In the cortex of a transgenic mouse model for Parkinson's disease, NPT200-11 therapy reduced α-Syn aggregation and neuroinflammation (astrogliosis). Additionally, NPT200-11 improved striatal Dopamine Transporter (DAT) levels and motor performance (Levenson et al., 2016). NPT088 decreased protein aggregation in an animal model of Parkinson's disease. It was assessed in a phase I clinical trial with individuals with mild-to-moderate AD (Michelson et al., 2019). In spite of NPT200-11's encouraging clinical results, the discovery of SMSIs for PD is imperative in the next upcoming years.

ASOs or antisense oligonucleotides

By upregulating the degradation of α-Syn messenger RNA levels (mRNA), which can delay the onset of PD, ASOs can also is utilized to slow down the disease's progression. Here's an additional technique to lower the expression of the SCNA (α-Syn gene). Uehara et al. created an ASO with improved stability and cellular absorption in vivo that targets the α-Syn gene using amido-bridged Nucleic Acid (AmNA). AmNA-ASO effectively reduced the amounts of α-Syn mRNA and protein (Uehara et al., 2019). Subsequent investigation revealed that mouse brainstem monoamine nuclei's native α-Syn mRNA and protein levels were decreased by triomonoamine reuptake inhibitor indatraline conjugated with ASO and small interfering RNA sequences that specifically target norepinephrine or serotonin (5-HT) neurons (Alarcón-Arís et al., 2018).

Beta2-Adrenoreceptor (β2AR) Agonists

Early in the 1990s, open-label trials were conducted to evaluate the brain-penetrant asthma medicine salbutamol, a β2AR agonist, in an effort to make the first clinical attempts to utilize β-adrenergic agonists in Parkinson's disease (Patterson et al., 2022). In 2003, additional studies validated the synergistic effects of β2AR agonists with L-DOPA. By objectively evaluating endogenous gene expression, a novel mechanism has been postulated for how β2AR agonists regulate the α-Syn gene and reduce its production, accumulation and deposition. A lower chance of acquiring Parkinson's Disease (PD) was linked to salbutamol during the 11-year follow-up. Alternatively, a β-adrenergic antagonist called propranolol was linked to a higher risk (Thenganatt and Jankovic, 2016). Evidence from Israeli and Norwegian populations also contributed to these conclusions, indicating that β2AR antagonist-treated patients had an elevated chance of Parkinson's illness and β2AR agonist-treated patients had a decreased risk (Gronich et al., 2018). β2AR agonists have been suggested to have a neuroprotective impact through immunomodulatory effects because their stimulation of astrocytes through adrenergic stimulation causes the synthesis of additional proteins or trophic factors connected to glutamate-induced excitotoxicity (Laureys et al., 2010).

The receptor for Lymphocyte-Activation Gene 3 (LAG3)

An intracytoplasmic portion and four domains that resemble extracellular Immunoglobulin (Ig) (D1-D4) are features of the transmembrane protein LAG3, also known as CD223 (Andrews et al., 2017). Largely expressed on microglia and neuronal cells, LAG3 has recently been connected to the etiology of Parkinson's disease, specifically in relation to α-Syn transmission, even if its exact function is yet unknown. Out of the three transmembrane protein candidates that were discovered, about binding to α-Syn PFFs that are exogenous rather than α-Syn monomers, LAG3 demonstrated the highest level of selectivity. By attaching to LAG3, α-Syn-biotin PFF caused neurotoxicity to be distributed through endocytosis and neuronal transmission followed (Angelopoulou et al., 2020). The neuroinflammatory mechanisms that contribute to the pathogenesis of Parkinson's illness may involve LAG3. In a newest Chinese population study, serum levels of LAG3 were considerably greater in patients with Parkinson's disease than in sex- and age-matched control groups as well as those with essential tremor. This finding raises the possibility that LAG3 is a promising molecular biomarker of Parkinson's disease (Cui et al., 2019).

Enhancing Autophagy

Mammalian Target of Rapamycin (mTOR) Signaling

Autophagy is regulated at multiple stages by the mTOR signaling pathway (Zhu, 2019). The different stages of Parkinson's disease are associated with both activation and inactivation of mTOR signaling. As mentioned before, autophagy is necessary for the breakdown of α-Syn. Overexpression of α-Syn increases mTOR activity, which in turn limits autophagy. Patients with α-Syn accumulation was found to have higher levels of mTOR protein expression in the temporal cortex. On the other hand, the elevated mTOR activity brought on the overexpression of α-Syn was diminished by the mTOR inhibitor rapamycin (Gao et al., 2015). However; a stress-related protein called RTP801/REDD1 dramatically lowers mTOR activity, which results in neuronal death. It was discovered that PD patients' substantia nigra pars compacta neurons have higher levels of RTP801 (Malagelada et al., 2006). Early studies on the combination of rapamycin and L-DOPA were carried out in an animal model with Parkinson's disease. Thankfully, it did not result in increased mTOR activity or decreased L-DOPA-induced dyskinesia (Calabrese et al., 2020). Therefore, Treatment with L-DOPA for Parkinson's disease is supported by science when paired with autophagy activation to improve α-Syn breakdown and rapamycin-induced reduction of mTOR signaling. Rapamycin protected neurons in Parkinson's disease-stricken mice by suppressing mTOR and increasing autophagy flux, which blocked RTP801 translation (Bové et al., 2011).

Inhibition of Cellular Homolog of ABL1 (c-Abl)

Tyrosine kinases from the ABL (Abelson murine leukemia virus oncogene) family are found in the cytoplasm and nucleus, which includes the c-Abl. It performs a variety of physiological functions, including autophagy, DNA repair, cytoskeleton dynamics, cell growth and receptor endocytosis (González-Martín et al., 2021). The importance of c-Abl biology in the central nervous system extends beyond cerebellar development to include neurite growth, synapse creation and neuronal proliferation. DA stress and DA neurotoxins cause phosphorylation of E3 ubiquitin ligase PRKN by activating c-Abl tyrosine kinase. Consequently, PRKN ubiquitination is inhibited and its protective effect is compromised (Abushouk et al., 2018). Microglial cells are rendered inactive and their production of pro-inflammatory mediators is reduced by c-Abl suppression. Furthermore, it increases autophagy to improve α-Syn clearance, suggesting a role for c-Ab1 inhibition in Parkinson's disease therapy (Hebron et al., 2013). Additionally, brain samples taken from people with Parkinson's illness showed activation of c-Abl, suggesting a pathophysiological role for the disease. Three c-Abl inhibitors have been investigated thus far as potential therapies for Parkinson's disease modification: imatinib, nilotinib and bafetinib (Breedveld et al., 2005).

RhoA-ROCK Signaling

The signaling protein RhoA is involved in the synthesis of actin, membrane trafficking and inflammation, among other physiological activities. The main RhoA downstream effectors are ROCK I and II (Villar-Cheda et al., 2012). RhoA/ROCK signaling may activate microglial cells, which could lead to DA depletion. When Rho kinase is activated, microglia's ROCK activity is increased, raising ROS levels and, in turn, inflammatory cytokines are released (Roser et al., 2017). RhoA-ROCK can block cofilin, which results in DA depletion (Tilve et al., 2015). The actin-binding protein cofilin is necessary for the depolymerization of actin filaments and, as a result, the prevention of actin filament elongation. Rho increases the polymerization of actin filaments by removing cofilin's ability to bind actin. Actin has been found in cytoplasmic α-Syn aggregates, leading to an increasing body of evidence suggesting a connection between PD and actin dynamics (Moussaud et al., 2014). Therefore, it is believed that ubiquitous RhoA/ROCK contributes to Parkinson's disease.

Promoting Neuroprotection

L-type Voltage-dependent Ca2+ Channel (L-VDCC)

By lowering mitochondrial stress, L-VDCC antagonists prevent MPTP-induced degeneration in SN neurons (Ilijic et al., 2011). As SN neurons age, they become dependent on L-VDCCs and Ca2+, which makes them vulnerable to neurotoxicity that L-VDCC antagonists can prevent. Additionally, α-Syn causes dysregulation of Ca2+, which in turn causes α-Syn aggregation (Lautenschläger et al., 2018). Research revealed that PD risk was decreased in patients receiving L-VDCC antagonist treatment. Moreover, microglia' transitioning the immune effector state from "rest" to "active" is regulated by intracellular Ca2+ (Hopp, 2021).

Agonists of Glucagon-Like Peptide-1 (GLP-1)

The GLP-1 receptor, also known as GLP-1R, is present in every other tissue except the pancreas. Seven transmembranes make up the GLP-1R class B G protein-coupled receptor. It initiates the process of activating protein kinase A (PKA) by increasing intracellular cAMP levels on neuronal cells. Moreover, it starts the PI3K/AKT signaling pathway's activity. Several downstream targets, such as the forkhead box protein O1 and glycogen synthase kinase-3 beta, are influenced by these pathways, which are essential to Parkinson's disease's degenerative processes and maintain an antiapoptotic cell survival pathway (Athauda and Foltynie, 2016).

Peroxisome Proliferator-Activated Receptors (PPARs) Agonists

PPARG, PPARG and PPARG/δ are the three ligand-activated transcription factors (PPARs) in the nuclear hormone receptor superfamily (Tyagi et al., 2011). Several research conducted both in vivo and in vitro have indicated that PPAR agonists may have neuroprotective advantages (Vega et al., 2000). It has been found that via reducing MAO-B activity, the PPARγ agonist pioglitazone protects DA neurons against MPTP and prevents MPTP from being converted to 1-Methyl-4-Phenylpyridinium (MPP+) (Chaturvedi and Beal, 2008). Pioglitazone helps the brain's mitochondrial potential and DA neuronal activity by reducing oxidative damage (Ulusoy et al., 2011).

Iron Chelators

PD patients' SN neurons have been found to accumulate iron, which is thought to be a disease-causing process related to the severity of the condition (Hayflick et al., 2018). Transferring iron from the cytoplasm to inclusions rich in α-Syn, overexpression of α-Syn results in an increase in intracellular iron levels. This causes α-Syn to combine and form fibrils more quickly, most likely as a result of increased α-Syn protein synthesis (Lingor et al., 2017). Moreover, ROS can be produced by iron. Therefore, iron elimination from the SN could halt the illness's progression. Preclinical studies indicate that iron chelators that are BBB-permeable, which remove excess iron, could be used as disease-modifying medications to treat Parkinson's disease (Dexter et al., 2011). A study that employed a Parkinson's disease model in mice with MPTP induction found that dexteroamine treatment significantly improved behavioral deficits and increased DA neuron survival.

Targeting Neuroinflammation

Phosphodiesterase 10A (PDE10A)

The medium spiny neurons in PDE10A are the target of striatal enzyme hydrolyzing cAMP and cGMP (Fujishige et al., 1999). PDE10A controls DA signaling in addition to a variety of other brain functions, such as synaptic plasticity, ion conductance. PDE10A deficit was linked to PDE10A and dopaminergic activity may be related, according to DAT deficiency in Parkinson disease patients' striatum who were treated with L-DOPA early on and de novo (Giorgi et al., 2008). Conversely, papaverine, a PDE10A inhibitor decreased the mortality of DA neurons by enhancing the production of neurotrophic factors, including B cell lymphoma 2, PKA signaling regulates both Brain-Derived Neurotrophic Factor (BDNF) and Glial cell line-Derived Neurotrophic Factor (GDNF) (Lee et al., 2019).

TLRs

There is growing evidence connecting PD and TLR2 and TLR4. In PD patients' postmortem brain tissue, TLR2 levels were elevated. Moreover, the TLR2 agonist PAM3CSK4 stimulates neuronal TLR2 and raises endogenous α-Syn levels in conjunction with elevated p62, a hallmark of the autophagy/lysosomal pathway (Kim et al., 2015).

CONCLUSION

Parkinson's disease has a wide spectrum of symptoms and complicated underlying biological causes, making it an ongoing challenge to treat. Although the current management options focus on symptom alleviation, novel approaches that target autophagy enhancement, neuroprotection, α-synuclein aggregation and neuroinflammation regulation provide intriguing paths for future therapeutic development. With more study to be done to fully understand the pathophysiology of Parkinson's disease, these novel medicines may be able to alter the course of the disease and enhance the quality of life for those who are afflicted.

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Kulkarni, V., Kumari, R. T. S., Muchandi, S. S., Nyamagoud, S. B., Nanjappaiah, H. M., Hooli, V. J., Tadkal, S. S., & Bali, P. N. (2026). Exploring Novel Emerging Therapeutic Strategies for Parkinson’s Disease: A Narrative Review. International Journal of Pharmaceutical Investigation, 16(3), 880–884. https://doi.org/10.5530/ijpi.20261067