inPentasomes: An innovative nose-to-brain pentamidine delivery blunts MPTP parkinsonism in mice

Rinaldi, Federica; Seguella, Luisa; Gigli, Silvia; Hanieh, Patrizia Nadia; Favero, Elena Del; Cantù, Laura; Pesce, Marcella; Sarnelli, Giovanni; Marianecci, Carlotta; Esposito, Giuseppe; Carafa, Maria

doi:10.1016/j.jconrel.2018.12.007

Cited by 45 publications

(35 citation statements)

References 31 publications

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“…PTM administration has also been shown to ameliorate clinical and/or neuropathologic/biomolecular parameters in other disorders involving the nervous system, such as AD, PD, sepsis-associated encephalopathy, and bowel inflammation, where its action has been reasonably attributed to the block of S100B activity [49][50][51]. In general, variations/manipulations of S100B concentration have been shown to directly correlate with clinical symptoms and/or biomolecular/pathological parameters of these disorders, which depend, as far it is known, on etiologic factors different from those hypothesized for MS, but that share with MS the occurrence of neuroinflammatory processes [5,52].…”

Section: Discussionmentioning

confidence: 99%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

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Section: Discussionmentioning

confidence: 99%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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“…In an attempt to provide a novel pharmacological approach to ameliorate PD induced by subchronic MPTP administration in C57BL-6J mice, a group of researchers developed a non-invasive intranasal delivery system, composed of chitosan coated niosomes with entrapped pentamidine (inPentasomes). The study demonstrated that inPentasomes, because of their capability to inhibit glial-derived S100B activity, rescued the dopaminergic neuronal loss and reduced the severity of neuroinflammation occurred in the nigrostriatal pathway, which subsequently led to a significant improvement in parkinsonian motor dysfunctions [61]. Another similar investigation reported the preparation of drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery using thin film hydration method.…”

Section: Niosomesmentioning

confidence: 91%

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

et al. 2020

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Although the global prevalence of neurological disorders such as Parkinson's disease, Alzheimer's disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs' entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices. Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neurodegenerative disease, leading to the development of bradykinesia and tremors of cardinal motor functions ( Figure 2) [3]. PD models specifically show a decrease in dopamine transporters, which are responsible for dopamine uptake by dopaminergic neurons and progression of neuronal communications. Reduced Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neuro...

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“…Rinaldi et al (2019) administered a cumulative 100 mg of MPTP/kg intraperitoneally in male C57Bl/6 J mice models and evaluated the inPentasomes effect against MPTP. They applied the open-field test and pole test to analyze the motor deficits in mice and revealed that the inPentasomes intranasal administration (1 or 4 μg/kg) inhibited the motor impairments by MPTP in a dose-dependent manner [ 154 ]. Nataraj et al (2016) administered a cumulative dose of 120 mg of MPTP/kg, intraperitoneally (30 mg/kg, four injections) in male C57BL/6 mice, and evaluated the Lutein protective effect against MPTP.…”

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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inPentasomes: An innovative nose-to-brain pentamidine delivery blunts MPTP parkinsonism in mice

Cited by 45 publications

References 31 publications

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

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