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Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.

ABSTRACT: The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson's disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effects. FMT-SLNs-PS80 was prepared by solvent injection method, the formulation was optimized by using Box-Behnken design and characterized by measuring drug content, entrapment efficacy, particle size, zeta potentials and poly dispersibility. The FMT-SLNs-PS80, significantly decreases the SNCA expression, mitochondrial membrane damage and rotenone induced changes in oxidative (SOD, CAT, GSH and ROS) stress markers in SH-SY5Y cell lines. The ex vivo permeation study of the formulation using everted chicken ileum exhibited a steady state flux. The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT. The anti-Parkinson's efficacy studies of the formulation in mice showed a significant neuroprotection against rotenone-induced changes in behavioural and biochemical parameters. Further, the histopathological analysis of mice brain confirms a significant neuroprotective benefit. The present study successfully establishes the brain targeted delivery and anti-Parkinson's therapeutic efficacy of FMT-SLNs-PS80.

SUBMITTER: Sola P

PROVIDER: S-EPMC10651909 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.

Sola Piyong P Garikapati Kusuma Kumari KK Krishnamurthy Praveen Thaggikuppe PT Kumari Mamta M

Scientific reports 20231115 1

The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson's disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effec ...[more]

PMID: 37968340

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Project description:Acetylcholinesterase (AChE) inhibitors such as donepezil, galantamine and rivastigmine are used for the management of dementia in Alzheimer's Disease (AD). These drugs elevate endogenous acetylcholine (ACh) levels at the M1 muscarinic receptor in the brain to achieve therapeutic benefits. However, their side effects, such as nausea, vomiting, dizziness, insomnia, loss of appetite, altered heart rate, etc., are related to non-specific peripheral activation of M2-M5 muscarinic subtypes. It is logical, therefore, to develop drugs that selectively activate brain M1 receptors. Unfortunately, the orthosteric site homology among the receptor subtypes does not permit this approach. An alternative approach is to use positive allosteric modulator (PAM) of M1 receptors like benzyl quinolone carboxylic acid (BQCA). PAMs although devoid of M1 agonist activity, however, when bound, enhance the binding affinity of orthosteric ligand, Ach. The current challenge with PAMS is their low brain half-life, permeability, and higher elimination rates. This study reports active targeting of brain M1 receptors using surface modified nano lipid-drug conjugates (LDC) of M1 PAM, BQCA, to treat AD. Polysorbate-80 (P-80) surface modified stearylamine (SA)-BQCA conjugated nanoparticles (BQCA-SA-P80-NPs) were prepared by conjugating BQCA to SA, followed by the formation of nanoparticles (NPs) using P-80 by solvent injection method. The BQCA-SA-P80-NPs are near-spherical with a particle size (PS) of 166.62 ± 1.24 nm and zeta potential (ZP) of 23.59 ± 0.37 mV. In the in vitro cytotoxicity (SH-SY5Y cells) and hemolysis assays, BQCA-SA-P80-NPs, show acceptable safety and compatibility. In mice, Alzheimer's model, BQCA-SA-P80-NPs significantly prevent STZ induced changes in memory, neuronal Aβ1-42, p-Tau, APP, NF-κB, and BACE levels and neuronal cell death, when compared to untreated disease control and naïve BQCA treated group. Further, BQCA-SA-P80-NPs significantly improve the therapeutic efficacy of AChE inhibitor, donepezil (DPZ), indicating its potentiating effects. In vivo biodistribution studies in mice show selective accumulation of BQCA-SA-P80-NPs in the brain, suggesting an improved brain bioavailability and reduced peripheral side effects of BQCA. The study results demonstrate that BQCA-SA-P80-NPs can improve brain bioavailability and therapeutic efficacy of BQCA in AD.

Dataset Information

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.

Publications

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.

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