Search Results (48)

Non-invasive drug delivery for ocular diseases remains a significant challenge in ophthalmology, as conventional eye drops offer less than 5% bioavailability due to pre-corneal barriers and the corneal epithelium. This review explores the intranasal (IN) route as a promising strategy for targeting both the anterior and posterior segments of the eye. The IN route leverages several distinct pathways: the nasolacrimal reflex for remote physiological stimulation; the “neural bridge” through the cribriform plate, allowing direct perineural and vascular transport via the olfactory and trigeminal nerves to bypass the blood–retinal barrier; and systemic absorption that avoids hepatic first-pass metabolism. Pre-clinical evidence indicates that IN administration of agents such as erythropoietin, nerve growth factor, and insulin achieves superior retinal concentrations compared to topical or systemic dosing, offering neuroprotection in models of retinal degeneration and glaucoma. Clinically, varenicline nasal spray is already FDA-approved for dry eye disease, while intranasal steroids demonstrate a favorable ocular safety profile without significantly increasing intraocular pressure. Although limited by mucociliary clearance and small delivery volumes, the IN route offers a painless, non-invasive alternative to intraocular injections, potentially enhancing patient compliance. Future advancements in mucoadhesive nanocarriers are essential to optimize drug residence time and realize the full potential of nose-to-eye delivery in chronic ophthalmic care. Full article

Background: Alzheimer’s disease (AD) remains an incurable disorder with severe clinical consequences. The type 3 diabetes hypothesis posits that AD may constitute a neuroendocrine disorder driven by disrupted insulin and insulin-like growth factor signaling. Amyloid pathogenesis in AD is characterized by the accumulation of beta-amyloid (Aβ) monomers, their subsequent oligomerization, and amyloid deposition. One of the causes of Aβ accumulation is disruption of amyloid precursor protein (APP) processing due to imbalance in ADAM10 and BACE1 expression. In recent years, increasing attention has been devoted to investigating the role of environmental factors in AD pathogenesis. The receptor for advanced glycation end products (RAGE) serves as a key molecular link between environmental exposure and neuroinflammatory pathology. Formaldehyde (FA) is one of the most widespread environmental pollutants. Its involvement in amyloid plaque formation has been previously reported; however, the molecular mechanisms underlying this process remain insufficiently understood. Moreover, most available data are based on prolonged FA exposure, whereas industrial FA emissions are often short-term. The objective of this study was to determine whether brief intranasal administration of FA, modeling episodic industrial pollution, induces RAGE-mediated neuroinflammation and amyloid deposition in CD1 mice. Methods: Mice received intranasal FA at environmentally relevant 0.02 mg/day or 0.2 mg/day doses for seven days; an additional group was co-treated with insulin. Cognitive function was assessed using passive avoidance (PA) and radial arm maze (RAM) tests, and synaptic plasticity was evaluated by electrophysiology. Hippocampal tissue was analyzed for RAGE expression, ADAM10/BACE1 gene balance, Aβ42 monomer levels, and amyloid deposits using optimized Thioflavin-S (Th-S) staining. Results: We observed cognitive decline in mice receiving intranasal FA administration. Elevated blood glucose levels were also observed following intranasal FA exposure. Sustained impairment of glucose metabolism led to overexpression of the RAGE in the hippocampus. There was also an imbalance of ADAM10 and BACE1 expression in the hippocampus. This was caused by overexpression of RAGE, as the enhanced interaction of the ligand and RAGE is a key factor disrupting this balance. Finally, Th-S staining confirmed amyloid deposition in mice subjected to intranasal FA exposure. Conclusions: This study provides new insights into the RAGE-mediated mechanisms by which FA contributes to the pathogenesis of AD. Full article

Insulin acts in the brain to promote satiety. Aging individuals may have brain insulin resistance and altered appetite perceptions. However, it is unclear if exercise impacts cerebral reward centers and appetite perception in middle-aged to older individuals. Purpose: To assess whether a single exercise bout alters cerebral blood flow (CBF) in reward centers in relation to appetite perceptions. Methods: Fifteen sedentary adults (12F; ~56 ± 2y; ~31 ± 1 kg/m²) completed a control and acute exercise condition (70% maximal oxygen consumption) in a randomized, counterbalanced order in the evening. Following an overnight fast, CBF in the accumbens, thalamus, and amygdala (pCASL MRI) was evaluated before and after intranasal insulin spray (INI, 40 IU) administration. Plasma glucose and insulin as well as an appetite visual analog scale (VAS) were assessed at fasting, 30, and 90 min post-INI, as well as at 30 min intervals of a 120 min 75 g oral glucose tolerance test (OGTT). Total area under the curve (tAUC) was calculated. Results: Exercise tended to lower blood glucose (p = 0.072) and plasma insulin (p = 0.007) tAUC, compared with rest. Exercise also raised right thalamus (p = 0.029) and left amygdala CBF (p = 0.023). The rise in fasting CBF in these regions, and the accumbens, correlated with reduced insulin tAUC (r = −0.55 to −0.73, p < 0.050). Although there was no difference in hunger, satisfaction, fullness, or prospective food consumption after exercise, changes in INI-stimulated thalamus CBF related to fullness tAUC after exercise (r = −0.57, p = 0.044). Conclusions: A single exercise bout might increase fasting CBF in some brain regions associated with appetite perception through a potential insulin-related mechanism. Full article

Intranasal drug delivery represents a transformative “backdoor” to the brain, bypassing the blood–brain barrier (BBB) that bars 98% of small molecules and nearly all large biopharmaceuticals. By harnessing the unique anatomy of the olfactory and trigeminal nerves, therapeutics can travel directly from the nasal cavity to the central nervous system, achieving therapeutic concentrations without the systemic toxicity of traditional routes. Clinical and preclinical evidence highlight the efficacy of intranasal insulin (INI) in treating Alzheimer’s disease (AD) and delirium, with studies showing significant improvements in cognitive scores and reduced hospital stays (7.9 vs. 12.9 days; p = 0.014). Additionally, other peptides can be administered intranasally like oxytocin, neuropeptide Y, and novel metabolic modulators for neuroprotection and affective disorders (AD, autism, Down syndrome). Despite these promises, critical translational gaps remain, including anatomical differences between macrosmatic rodents and microsmatic humans, and significant sex-based dosing dimorphism. The ease of intranasal administration introduces profound bioethical dilemmas regarding neuroenhancement, authenticity, and informed consent in vulnerable populations. The current literature concludes that realizing the full potential of nose-to-brain (N2B) therapy requires a commitment to precision medicine, utilizing specialized delivery devices and objective biomarkers to ensure safe and equitable clinical application. Full article

Background: Compared with normal weight, obese individuals display a variety of deviant measures in neuroenergetic status, food intake behavior, glucose metabolism, and circulating vitamin C levels. A chronically lowered neuroenergetic content is associated with increased food intake and disturbed glucose metabolism in obesity. In turn, a vitamin C deficiency found in obesity may be connected to these disturbances. Therefore, we investigated the effects of vitamin C application in the human brain. Methods: We intranasally applied vitamin C (80 mg ascorbic acid/day) vs. placebo for 8 consecutive days in 15 normal weight (BMI 20–25 kg/m²) and 15 obese (BMI > 30 kg/m²) men. The neuroenergetic content of adenosine triphosphate (ATP) and phosphocreatine (PCr) was assessed by ³¹phosphorous magnetic resonance spectroscopy, a non-invasive real-time technique to measure high-energy phosphate compounds in living tissues. Peripheral vitamin C, glucose, and insulin concentrations were measured, and spontaneous food intake was quantified by the standardized buffet test. Results: In the obese group, vitamin C application acutely suppressed the physiological insulin response on the first experimental day (p = 0.003). The following eight days of intranasal vitamin C led to higher serum vitamin C concentrations as compared to placebo (p = 0.011), compensated for the missing food intake-induced serum vitamin C rise (p ≤ 0.002), and attenuated a PCr decline (p = 0.008) in this group. Correlation analyses revealed a general link between serum vitamin C concentrations and the neuroenergetic state in both groups (p ≤ 0.033). Food intake was not influenced. Conclusions: Intranasal vitamin C application acutely improves insulin sensitivity, compensates for a vitamin C deficiency, and may act in a neuroprotective way in obese men. It could therefore be a future candidate as an adjuvant therapeutic option in obesity treatment. Full article

As a metabolism-controlling peptide, insulin affects activity of almost all tissues in human organisms, including the ones located in the central nervous system. By modifying glucose uptake and processing, as well as inducing anabolic effects, insulin alters functions of various nerve centers. Data from numerous clinical trials prove that such actions can have positive influence on cognitive processes or might be utilized as measures to control appetite, mood, and blood flow, or to prevent unfavorable mental states associated with diminished ability to maintain homeostasis. The intranasal route of administration provides an efficient and targeted delivery method, allowing insulin to be applied directly to different brain regions via the nasal mucosa. Such an approach can also reduce the risk of potential adverse effects associated with this medication, including drops in plasma glucose levels. This review gathers clinical studies’ findings on intranasal insulin’s neuromodulatory properties and its efficacy as additional treatment measure in several neuropsychiatric disease entities. Full article

Background/Objectives: Nanoemulsions and microemulsions are promising drug delivery systems capable of enhancing the solubility, stability, and bioavailability of active pharmaceutical ingredients, particularly for central nervous system (CNS) disorders. This study presents a bibliometric analysis of scientific publications on intranasal nanoemulsions from 2004 to 2024, based on data from the Scopus database. Methods: A total of 379 articles were analyzed using Bibliometrix and VOSviewer to identify publication trends, leading countries and institutions, prominent journals, and keyword networks. Results: Publications grew significantly over the last decade, with India, the United States, and China leading in volume. Keyword analysis revealed strong thematic clusters related to “brain targeting,” “drug delivery,” and “intranasal administration,” highlighting this route’s potential for bypassing the blood–brain barrier. The most studied compounds included curcumin, quercetin, carbamazepine, diazepam, and insulin, each with therapeutic applications in neurodegenerative and psychiatric disorders. Conclusions: The findings highlight growing interest in intranasal nano- and microemulsions as a non-invasive and efficient CNS delivery strategy. Future research can bridge translational gaps, enhancing efficacy and safety while meeting regulatory expectations for patient-centered drug development. This study provides a comprehensive overview of current trends and serves as a guide for advancing innovative intranasal delivery platforms. Full article

Background: This paper investigates the effect of intranasal insulin administration on brain glutathione (GSH) levels and elucidates the potential mechanism by which insulin enhances antioxidant defenses in the brain. Methods: C57BL/6J mice were intranasally administered insulin (2 IU/day) or saline for 7 days. GSH levels were measured in the brain and liver. Blood glucose concentrations and daily food intake were also monitored. Protein levels of excitatory amino acid carrier-1 (EAAC1), its interaction with glutamate transport-associated protein 3-18(GTRAP3-18), and activated AMP-activated protein kinase (AMPK) were assessed. Results: Insulin-treated mice exhibited significantly higher GSH levels in the hippocampus and midbrain compared to saline-treated controls, while no significant differences were found in liver GSH levels, blood glucose concentrations, or food intake. EAAC1 expression increased in both the cytosolic and plasma membrane fractions of insulin-treated mouse brains. Furthermore, the interaction between EAAC1 and its negative regulator, GTRAP3-18, along with activated AMPK levels, was reduced in insulin-treated mice. Conclusions: Intranasal insulin administration enhances brain GSH levels through a mechanism involving EAAC1 upregulation and reduced AMPK activation. These findings suggest that intranasal insulin could be a promising strategy for enhancing antioxidant defenses against neurodegeneration in the brain. Full article

Two common mechanisms contributing to multiple neurological disorders, including Alzheimer’s disease, are brain glucose hypometabolism (BGHM) and brain iron accumulation (BIA). Currently, BGHM and BIA are both widely acknowledged as biomarkers that aid in diagnosing CNS disorders, distinguishing between disorders with similar symptoms, and tracking disease progression. Therapeutics targeting BGHM and BIA in Alzheimer’s disease can be beneficial in treating neurocognitive symptoms. This review addresses the evidence for the therapeutic potential of targeting BGHM and BIA in multiple CNS disorders. Intranasal insulin, which is anti-inflammatory and increases brain cell energy, and intranasal deferoxamine, which reduces oxidative damage and inflammation, represent promising treatments targeting these mechanisms. Both BGHM and BIA are promising therapeutic targets for AD and other CNS disorders. Full article

Background/objectives: The blood–brain barrier (BBB) significantly limits the treatment of central nervous system disorders, such as schizophrenia, by restricting drug delivery to the brain. This study explores the potential of intranasal clozapine-loaded lipid nanocapsules (IN LNCs_Clo) as a targeted and effective delivery system to the brain. Methods: LNCs_Clo were prepared using the phase inversion technique and characterized in terms of size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. The pharmacokinetic, safety, and pharmacodynamic effects of LNCs_Clo were then evaluated in a rat model through intranasal (IN) administration and compared with those of oral and intravenous (IV) Clo solutions. Results: LNCs_Clo were prepared using a phase inversion technique, resulting in a nanocarrier with a particle size of 28.6 ± 3.6 nm, homogenous dispersion, and high EE% (84.66 ± 5.66%). Pharmacokinetic analysis demonstrated that IN LNCs_Clo provided enhanced Clo brain bioavailability, rapid CNS targeting, and prolonged drug retention compared to oral and intravenous routes. Notably, the area under the curve (AUC) for brain concentration showed more than two-fold and eight-fold increases with LNCs_Clo, compared to IV and oral solutions, respectively, indicating improved brain-targeting efficiency. Safety assessments indicated that LNCs_Clo administration mitigated Clo-associated metabolic side effects, such as hyperglycemia, insulin imbalance, and liver enzyme alterations. Additionally, pharmacodynamic studies showed that LNCs_Clo significantly improved antipsychotic efficacy and reduced schizophrenia-induced hyperactivity, while preserving motor function. Conclusions: These results highlight the potential of IN LNCs_Clo as a novel drug delivery system, offering improved therapeutic efficacy, reduced systemic side effects, and better patient compliance in the treatment of schizophrenia and potentially other CNS disorders. Full article

Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies. Full article

The nasal route of administration can bypass the blood–brain barrier in order to obtain a higher concentration in the brain, thus offering a feasible alternative route of administration for diseases associated with the central nervous system. The advantages of the intranasal administration and the potential favorable therapeutic effects of intranasally administered insulin led to the formulation of carboxymethyl chitosan (CMC) and sodium hyaluronate (NaHA) hydrocolloidal systems with insulin for nasal administration, targeting nose-to-brain delivery and the initial assessment of these systems. The influence of the formulation variables on the response parameters defined as surface properties, rheology, and in vitro release of insulin were analyzed using experimental design and statistical programs (Modde and Minitab software). The systems recorded good wetting and adhesion capacity, allowing the spread of the hydrocolloidal systems on the nasal mucosa. The samples had a pseudoplastic flow and the rapid release of the insulin was according to our objective. According to the physico-chemical characterization and preliminary assessment, these formulations are appropriate for administration on the nasal mucosa, but further studies are necessary to demonstrate the beneficial therapeutic actions and the safety of using intranasal insulin. Full article

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally. Full article

Insulin is a promising neuroprotector. To better understand the mechanism of insulin action, it was important to show its ability to diminish autophagic neuronal death in animals with brain ischemic and reperfusion injury. In forebrain ischemia and reperfusion, the number of live neurons in the hippocampal CA1 region and frontal cortex of rats decreased to a large extent. Intracerebroventricular administration of the autophagy and apoptosis inhibitors to ischemic rats significantly increased the number of live neurons and showed that the main part of neurons died from autophagy and apoptosis. Intranasal administration of 0.5 IU of insulin per rat (before ischemia and daily during reperfusion) increased the number of live neurons in the hippocampal CA1 region and frontal brain cortex. In addition, insulin significantly diminished the level of autophagic marker LC3B-II in these forebrain regions, which markedly increased during ischemia and reperfusion. Our studies demonstrated for the first time the ability of insulin to decrease autophagic neuronal death, caused by brain ischemia and reperfusion. Insulin administered intranasally activated the Akt-kinase (activating the mTORC1 complex, which inhibits autophagy) and inhibited the AMP-activated protein kinase (which activates autophagy) in the hippocampus and frontal cortex of rats with brain ischemia and reperfusion. Full article

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer’s disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions. Full article