Drug Targeting to the Brain: Transfer of Picolinic Acid Along the Olfactory Pathways

Bergström, Ulrika; Franzén, Anna; Eriksson, Catarina; Lindh, Christian; Brittebo, Eva B.

doi:10.1080/1061186021000038346

Cited by 14 publications

(12 citation statements)

References 29 publications

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“…This connection may therefore be a portal of entry of drugs and toxicants into the brain, thus circumventing the blood-brain barrier. A significant uptake of some drugs and chemicals has been reported in the ipsilateral olfactory bulb after a unilateral intranasal instillation (Dahlin et al 2000;Bergstrom et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants

Piras

Franzén

Fernández

et al. 2003

J Histochem Cytochem.

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We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

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Section: Discussionmentioning

confidence: 99%

Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants

Piras

Franzén

Fernández

et al. 2003

J Histochem Cytochem.

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“…Bergstrom et al [95] have also reported the transport of picolinic acid along the olfactory pathways after administration via intranasal and intravenous routes in mice. Autoradiography demonstrated rapid uptake of radioactivity in the olfactory nerve layer and in the ipsolateral olfactory bulb following intranasal administration.…”

Section: Delivery Of Non-peptide Molecules To the Cnsmentioning

confidence: 94%

Intranasal Drug Delivery for Brain Targeting

Vyas¹,

Shahiwala²,

Marathe³

et al. 2005

CDD

213

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Many drugs are not being effectively and efficiently delivered using conventional drug delivery approach to brain or central nervous system (CNS) due to its complexity. The brain and the central nervous system both have limited accessibility to blood compartment due to a number of barriers. Many advanced and effective approaches to brain delivery of drugs have emerged in recent years. Intranasal drug delivery is one of the focused delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Realization of nose to brain transport and the therapeutic viability of this route can be traced from the ancient times and has been investigated for rapid and effective transport in the last two decades. Various models have been designed and studied by scientists to establish the qualitative and quantitative transport through nasal mucosa to brain. The development of nasal drug products for brain targeting is still faced with enormous challenges. A better understanding in terms of properties of the drug candidate, nose to brain transport mechanism, and transport to and within the brain is of utmost importance. This review will discuss some pertinent issues to be considered and challenges to brain targeted intranasal drug delivery. A few marketed and investigational drug formulations will also be discussed.

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“…Since the olfactory bulb is not protected by the blood-brain barrier (Oberdorster et al 2004), this brain region is continuously exposed to airborne pollutants (Franco et al 2007). Airborne environmental contaminants as well as pharmaceuticals locally administrated on the nasal mucus may be directly transferred to the olfactory bulb along the axons of the olfactory neurons, as their dendrites project into the nasal mucus and their axons into the olfactory bulb (Bergstrom et al 2002;Eriksson et al 1999). Pathological alterations induced by airborne environmental toxicants may contribute to the initiation of protein aggregation in the olfactory bulb, which in turn triggers the spread of the pathology within the brain (Attems et al 2014).…”

Section: Introductionmentioning

confidence: 99%

The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) targets the olfactory bulb region

et al. 2020

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Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine if BMAA targets the olfactory system. Autoradiographic imaging showed a distinct localization of radioactivity in the right olfactory mucosa and bulb following a unilateral intranasal instillation of 3H-BMAA (0.018 µg) in mice, demonstrating a direct transfer of BMAA via the olfactory pathways to the brain circumventing the blood–brain barrier, which was confirmed by liquid scintillation. Treatment of mouse primary olfactory bulb cells with 100 µM BMAA for 24 h caused a disruption of the neurite network, formation of dendritic varicosities and reduced cell viability. The NMDA receptor antagonist MK-801 and the metabotropic glutamate receptor antagonist MCPG protected against the BMAA-induced alterations, demonstrating the importance of glutamatergic mechanisms. The ionotropic non-NMDA receptor antagonist CNQX prevented the BMAA-induced decrease of cell viability in mixed cultures containing both neuronal and glial cells, but not in cultures with neurons only, suggesting a role of neuron–glial interactions and glial AMPA receptors in the BMAA-induced toxicity. The results show that the olfactory region may be a target for BMAA following inhalation exposure. Further studies on the relations between environmental olfactory toxicants and neurodegenerative disorders are warranted.

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Drug Targeting to the Brain: Transfer of Picolinic Acid Along the Olfactory Pathways

Cited by 14 publications

References 29 publications

Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants

Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants

Intranasal Drug Delivery for Brain Targeting

The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) targets the olfactory bulb region

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