Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys

Iwasaki, Shinji; Yamamoto, Satoshi; Sano, Noriyasu; Tohyama, Kimio; Kosugi, Yukio; Furuta, Atsutoshi; Hamada, Takashi; Igari, Tomoko; Fujioka, Yasushi; Hirabayashi, Hideki; Amano, Nobuyuki

doi:10.1007/s11095-019-2613-8

Cited by 22 publications

(16 citation statements)

References 41 publications

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“…In contrast, the intranasal route provides a direct and noninvasive pathway to bypass the BBB, with increased intracerebral drug concentrations, decreased quantities, and few side effects observed 44 . Several proteins and polypeptides, such as BDNF and CNTF, have been reported that can efficiently enter the CNS target location through the intranasal route in a mouse model, 45 and it has also been demonstrated that the intranasal administration route could increase the delivery of low-permeable small molecules to the brain in both rats and monkeys, 46 and also to be effective in EcoHIV-infected mice and voluntary AD patients 47 , 48 . Although carrier and intrusive issues still need to be addressed, direct nose-to-brain drug delivery offers a potentially efficient strategy for AD treatment 44 .…”

Section: Discussionmentioning

confidence: 99%

Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model

Mai

Fan

Wang

et al. 2019

Molecular Therapy - Nucleic Acids

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Alzheimer's disease (AD) is the most common cause of dementia and cannot be cured. The etiology and pathogenesis of AD is still not fully understood, the genetics is considered to be one of the most important factors for AD onset, and the identified susceptible genes could provide clues to the AD mechanism and also be the potential targets. MicroRNA-146a-5p (miR-146a) is well known in the regulation of the inflammatory response, and the functional SNP of miR-146a was associated with AD risk. In this study, using a noninvasive nasal administration, we discovered that a miR-146a agomir (M146AG) rescued cognitive impairment in the APP/PS1 transgenic mouse and alleviated the overall pathological process in the AD mouse model, including neuroinflammation, glia activation, Ab deposit, and tau phosphorylation in hippocampi. Furthermore, the transcriptional analysis revealed that besides the effect of neuroinflammation, M146AG may serve as a multi-potency target for intervention in AD. In addition, Srsf6 was identified as a target of miR-146a, which may play a role in AD progression. In conclusion, our study supports that the nasal-to-brain pathway is efficient and operable for the brain administration of microRNAs (miRNAs), and that miR-146a may be a new potential target for AD treatment.

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Section: Discussionmentioning

confidence: 99%

Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model

Mai

Fan

Wang

et al. 2019

Molecular Therapy - Nucleic Acids

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“…Intranasal administration is an attractive route for drug delivery to the brain because it allows the direct transport of drugs from the nasal cavity to the brain parenchyma by bypassing systemic circulation [3][4][5][6][7][8]. This strategy has been called "nose-to-brain delivery".…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

et al. 2021

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We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas.

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“…Thus, in a study with rabbits and rats, intranasal administration of diazepam in a microemulsion formulation produced a homogenous drug distribution in the brain with concentrations in the olfactory bulb no greater than those in other brain regions or the brain as a whole [32]. In a separate study in rats, the relative exposure of midazolam in the olfactory bulb and olfactory tract following intranasal deposition of an aqueous suspension of midazolam was no different from the relative exposure in the rest of the brain, and the ratio of exposures following intranasal and intravenous delivery in the olfactory areas did not substantially exceed the ratio in the rest of the brain [28]. These results indicate minimal brain-to-nose delivery of the highly lipophilic benzodiazepines; the bulk of distribution to the brain is via the venous circulation.…”

Section: Discussionmentioning

confidence: 82%

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Żółkowska

Rogawski

2021

Neurotherapeutics

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Allopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

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Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys

Cited by 22 publications

References 41 publications

Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model

Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model

Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

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