Intranasal Treatment of Central Nervous System Dysfunction in Humans
TL;DR: In this paper, the intranasal delivery is proposed as a noninvasive option for delivering drugs to the central nervous system (CNS) with minimal peripheral exposure, which facilitates the delivery of large and/or charged therapeutics which fail to effectively cross the blood-brain barrier (BBB).
Abstract: One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.
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TL;DR: This review examines molecular and cellular mechanisms underlying the establishment of the blood-brain barrier, and examines how BBB dysfunction relates to neurological deficits and other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis, other neurodegenerative disorders, and acute CNS disorders.
Abstract: The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of t...
1,033 citations
TL;DR: Molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin are presented and an overview of neuroimaging studies indicating that disturbances in insulin metabolism and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy is provided.
Abstract: Research in animals and humans has associated Alzheimer’s disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism—such as insulin resistance in obesity, type 2 diabetes and AD—and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.
399 citations
Cites background from "Intranasal Treatment of Central Ner..."
...Another proposed transport mechanisms is via the rostral migratory stream [90]....
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TL;DR: This review presents some possibilities to enhance the drug penetration through the nasal barrier and summarizes some in vitro, ex vivo and in vivo technologies to test the drug delivery across the nasal epithelium into the brain.
393 citations
TL;DR: The latest works on various novel formulations loaded with various anti‐Alzheimer agents are discussed, which underlines the fact that majority of work related to the nose‐to‐brain delivery of anti‐AD drugs is limited only up to preclinical studies.
331 citations
TL;DR: There is a negative correlation between stress-induced behavioural disruption and cerebral NPY expression in animal models of post-traumatic stress disorder, which indicates a role in stress resilience, the ability to cope with stress.
311 citations
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TL;DR: A model is described that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
6,178 citations
TL;DR: It is shown that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions.
Abstract: Trust pervades human societies. Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics. In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country's institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success. Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions. We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks. On the contrary, oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. These results concur with animal research suggesting an essential role for oxytocin as a biological basis of prosocial approach behaviour.
3,202 citations
"Intranasal Treatment of Central Ner..." refers background in this paper
...coworkers who revealed that oxytocin increases trust in humans, thereby demonstrating its pro-social potential (53)....
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TL;DR: Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype.
1,353 citations
"Intranasal Treatment of Central Ner..." refers background in this paper
...PWS is a congenital disease that produces a variety of undesirable effects, including gross body weight gain (64)....
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TL;DR: Three peptides were administered intranasally and found that they achieved direct access to the cerebrospinal fluid (CSF) within 30 minutes, bypassing the bloodstream.
Abstract: Neuropeptides act as neuronal messengers in the brain, influencing many neurobehavioral functions1. Their experimental and therapeutic use in humans has been hampered because, when administered systemically, these compounds do not readily pass the blood–brain barrier, and they evoke potent hormone-like side effects when circulating in the blood2,3. We administered three peptides, melanocortin(4–10) (MSH/ACTH(4–10)), vasopressin and insulin, intranasally and found that they achieved direct access to the cerebrospinal fluid (CSF) within 30 minutes, bypassing the bloodstream.
1,259 citations
"Intranasal Treatment of Central Ner..." refers background in this paper
...In contrast to the intranasal administration of hydrophilic compounds, which typically results in low or no systemic exposure while targeting the brain (10), it can be difficult to avoid systemic exposure with an intranasally delivered small lipophilic molecule....
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...In addition, it causes rapid increases in CNS levels of these compounds, and for some—such as insulin—avoids any significant peripheral uptake (10)....
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...to assume that it gains access via a similar mechanism (10)....
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TL;DR: Results show that leptin is transported intact from blood to brain by a saturable system and inhibited the influx of 125I-leptin in a dose-dependent manner whereas unlabeled tyrosine and insulin, which have saturable transport systems, were without effect.
1,216 citations
"Intranasal Treatment of Central Ner..." refers background in this paper
...centrations in CSF, suggesting that the problem, at least in part, involves the quantities of leptin able to pass the BBB (48)....
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...In addition, peripheral administration of leptin fails to increase leptin concentrations in CSF, suggesting that the problem, at least in part, involves the quantities of leptin able to pass the BBB (48)....
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...Most significantly, it is difficult to impossible for many molecules, particularly large and/or charged ones, to enter the brain from the bloodstream due to the blood-brainbarrier (BBB), which keeps foreign materials out (1)....
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...Unlike insulin, oxytocin does not present with many unwanted systemic effects; however, because of the size of the molecule it is ineffective to administer it via the periphery, as it does not seem to pass the BBB in significant quantities (52)....
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...Plasma protein binding, another consequence of systemic administration, can also affect both the duration and intensity of a drug’s action, reducing its ability to efficiently cross the BBB (3)....
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