Intranasal delivery to the central nervous system: Mechanisms and experimental considerations

Dhuria, Shyeilla V.; Hanson, Leah R.; Frey, William H.

doi:10.1002/jps.21924

Cited by 1,008 publications

(835 citation statements)

References 154 publications

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“…40 The intranasal route of administration is a noninvasive method to target the CNS and has shown success in clinical trials for the treatment of cognitive diseases such as Alzheimer's and schizophrenia. 41 Thus, from a therapeutic perspective, intranasal administration of CpG offers a dosing strategy with superior clinical relevance for the prophylactic treatment of patients at high risk of suffering from cerebral ischemia, such as patients undergoing cardiovascular surgery.…”

Section: Discussionmentioning

confidence: 99%

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

Packard

Leung

Vartanian

et al. 2012

J Cereb Blood Flow Metab

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Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF.

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Section: Discussionmentioning

confidence: 99%

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

Packard

Leung

Vartanian

et al. 2012

J Cereb Blood Flow Metab

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“…Drug Deliv. (2014) 11 (6) points with respect to the initial activity and was plotted against time [25].…”

Section: Nasal Clearance Studymentioning

confidence: 99%

“…Drug Deliv. (2014) 11 (6) increased the absorption of drug in blood. However, BRC solution did not remain adhered to nasal mucosa due to lack of mucoadhesive agent and got cleared rapidly due to mucociliary clearance under normal circumstances.…”

Section: Optimised Nanoformulation Of Brc For Direct Nose-to-brain Dementioning

confidence: 99%

“…delivery has come to the forefront as an alternative to invasive delivery methods to bypass the BBB and target drugs directly to the brain. This may provide significant advantages such as non-invasiveness, bypassing BBB and decreasing systemic drug exposition, thereby reducing systemic side effects as compared to current conventional strategies [6,7]. The drug may be transported directly into the brain tissue (i.e., olfactory bulb) or the cerebrospinal fluid through the olfactory region of the nasal cavity [7,8].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery: biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry method

Shadab

Haque

Fazil

et al. 2014

Expert Opinion on Drug Delivery

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“…Instead, direct nose-to-brain delivery describes the phenomenon where drugs applied to the nasal cavity penetrate directly from the nasal cavity to the brain and cerebral spinal fluid (CSF) thus bypassing the blood in their first passage. Some possible advantages that can be gained through this nose-to-brain route are rapid distribution to the brain, lower systemic concentrations, and CNS delivery of drugs that do not cross the blood-brain barrier (BBB) (2). While the exact mechanisms of direct nose-to-brain transport are not completely understood, growing anatomical and experimental evidence suggests that drugs primarily utilize the nervous connections in the olfactory region of the nasal cavity in order to directly distribute to the CNS (3).…”

Section: Introductionmentioning

confidence: 99%

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Hoekman

2011

AAPS PharmSciTech

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Abstract. Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P=−3.1), and a hydrophobic drug, nelfinavir (log P=6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p<0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p<0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

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Intranasal delivery to the central nervous system: Mechanisms and experimental considerations

Cited by 1,008 publications

References 154 publications

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery: biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry method

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

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