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Drug delivery to the brain-just a sniff away
Newsdesk Drug delivery to the brain—just a sniff away Could a transnasal route be used for drug delivery to the brain? Jan Born (University of Lübeck, Germany) and colleagues report that intranasal administration of three neuropeptides —melanocortin(4–10), vasopressin, and insulin—to 36 healthy people resulted in accumulation of each peptide in the CSF within 30 min. Except for vasopressin, the researchers saw no increase in blood concentrations of the peptides over the same time period (Nat Neurosci 2002; 5: 514–6). William Frey (University of Minnesota, Minneapolis, MN, USA) notes that this research builds on results previously obtained in animal models and “provides more evidence that intranasal delivery may fundamentally alter the way we treat diseases and disorders of the CNS”. The more we learn about neuropeptides and how they function in the brain, the more likely it seems that some of them could be valuable therapeutic agents. However, delivery
Short-cut to the brain?
of neuropeptides, and indeed other therapeutic agents, to the brain is problematic because of the blood-brain barrier (BBB). Intracerebroventricular injection of drugs is one way to circumvent the BBB, but says Born, “for ethical reasons, this invasive technique can only be used in severely ill patients”. Intranasal delivery is a potential, non-invasive way to bypass the BBB. It has been known for years that some small molecules can pass directly from
the submucous space of the nose to the CSF of the olfactory lobe and then circulate within the CSF flow tracts of the brain. Born’s current work seems to extend this administration route to neuropeptides. “But, transnasal delivery does not deliver a drug deep into the brain parenchyma”, cautions William Pardridge (University of California, Los Angeles, CA, USA). “The drug is only delivered to the CSF and will be cleared back into the peripheral blood before there is time for it to be carried to brain tissue.” Born agrees that he has not directly demonstrated neuropeptide delivery to brain parenchyma in human beings, “but the results of animal studies indicate that nasally delivered peptides reach the more interior structures of the brain. We are now looking into the possibility of using imaging methods such as magnetic resonance spectroscopy to monitor neuropeptide delivery to brain structures in people.” Jane Bradbury
Psychiatric and neural impairment may cause rage attacks “Violence is a behaviour, not an illness”, stresses Mary Best (Children’s Hospital of Philadelphia, PA, USA), although Best and colleagues have recently reported evidence of a dysfunctional prefrontal circuit in patients with a rage disorder. But, say experts, the neural basis of anger remains unclear. Intermittent explosive disorder (IED) was characterised in 1980 as a psychiatric condition—it involves outbursts of aggression similar to those that sometimes occur in people with orbitofrontal lesions. Best’s team sought evidence of similar impairment in IED. The researchers tested 24 patients and 22 controls for dysfunction of the orbital/medial prefrontal cortex circuit by use of the Iowa Gambling Task, facial-emotion recognition, and odour detection tests, as well as control tests. Participants with IED had significantly reduced task performance but control-test results did not differ significantly
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between the groups. The IED patients had similar though less severe deficits to those in previous studies who had orbitofrontal and amygdala lesions (Proc Natl Acad Sci USA; published online May 28; DOI: 10.1073/ pnas.112604099). Detected deficits could contribute to symptoms of IED, the authors argue. “Patients had difficulty learning to consistently avoid making choices that were associated with high levels of punishment”, says Best, and when shown faces depicting various emotions, patients with IED were more likely than controls to attribute a negative emotion to a neutral facial expression. However, Andrew Lawrence (MRC Cognition and Brain Sciences Unit, Cambridge, UK) points out that perceptual impairments, or a more general deficit, are difficult to rule out from these studies. “Having said that”, says his colleague Andrew Calder, “the facial expression task provides the first
evidence of abnormal perception of negative facial expressions in IED.” This finding might be useful for therapy, says Best: “IED patients may have difficulty learning from punishment—this needs to be further explored for therapeutic value.” Best urges clinicians to consider IED in violent outbursts, “because treatment options are available which may prevent further violent episodes”. One treatment is selective serotonin-reuptake inhibitors. The authors speculate that their findings, together with other work, suggest a role for serotonin in aggression. Also, recent work by Lawrence and Calder implicates dopamine in the recognition of anger (Neuroreport 2002; 13: 881–84). Both neurotransmitters may act on the same neural circuit, although Lawrence stresses that other studies implicated the whole prefrontal cortex in aggression. Kelly Morris
THE LANCET Neurology Vol 1 July 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Short-cut to the brain?
of neuropeptides, and indeed other therapeutic agents, to the brain is problematic because of the blood-brain barrier (BBB). Intracerebroventricular injection of drugs is one way to circumvent the BBB, but says Born, “for ethical reasons, this invasive technique can only be used in severely ill patients”. Intranasal delivery is a potential, non-invasive way to bypass the BBB. It has been known for years that some small molecules can pass directly from
the submucous space of the nose to the CSF of the olfactory lobe and then circulate within the CSF flow tracts of the brain. Born’s current work seems to extend this administration route to neuropeptides. “But, transnasal delivery does not deliver a drug deep into the brain parenchyma”, cautions William Pardridge (University of California, Los Angeles, CA, USA). “The drug is only delivered to the CSF and will be cleared back into the peripheral blood before there is time for it to be carried to brain tissue.” Born agrees that he has not directly demonstrated neuropeptide delivery to brain parenchyma in human beings, “but the results of animal studies indicate that nasally delivered peptides reach the more interior structures of the brain. We are now looking into the possibility of using imaging methods such as magnetic resonance spectroscopy to monitor neuropeptide delivery to brain structures in people.” Jane Bradbury
Psychiatric and neural impairment may cause rage attacks “Violence is a behaviour, not an illness”, stresses Mary Best (Children’s Hospital of Philadelphia, PA, USA), although Best and colleagues have recently reported evidence of a dysfunctional prefrontal circuit in patients with a rage disorder. But, say experts, the neural basis of anger remains unclear. Intermittent explosive disorder (IED) was characterised in 1980 as a psychiatric condition—it involves outbursts of aggression similar to those that sometimes occur in people with orbitofrontal lesions. Best’s team sought evidence of similar impairment in IED. The researchers tested 24 patients and 22 controls for dysfunction of the orbital/medial prefrontal cortex circuit by use of the Iowa Gambling Task, facial-emotion recognition, and odour detection tests, as well as control tests. Participants with IED had significantly reduced task performance but control-test results did not differ significantly
140
between the groups. The IED patients had similar though less severe deficits to those in previous studies who had orbitofrontal and amygdala lesions (Proc Natl Acad Sci USA; published online May 28; DOI: 10.1073/ pnas.112604099). Detected deficits could contribute to symptoms of IED, the authors argue. “Patients had difficulty learning to consistently avoid making choices that were associated with high levels of punishment”, says Best, and when shown faces depicting various emotions, patients with IED were more likely than controls to attribute a negative emotion to a neutral facial expression. However, Andrew Lawrence (MRC Cognition and Brain Sciences Unit, Cambridge, UK) points out that perceptual impairments, or a more general deficit, are difficult to rule out from these studies. “Having said that”, says his colleague Andrew Calder, “the facial expression task provides the first
evidence of abnormal perception of negative facial expressions in IED.” This finding might be useful for therapy, says Best: “IED patients may have difficulty learning from punishment—this needs to be further explored for therapeutic value.” Best urges clinicians to consider IED in violent outbursts, “because treatment options are available which may prevent further violent episodes”. One treatment is selective serotonin-reuptake inhibitors. The authors speculate that their findings, together with other work, suggest a role for serotonin in aggression. Also, recent work by Lawrence and Calder implicates dopamine in the recognition of anger (Neuroreport 2002; 13: 881–84). Both neurotransmitters may act on the same neural circuit, although Lawrence stresses that other studies implicated the whole prefrontal cortex in aggression. Kelly Morris
THE LANCET Neurology Vol 1 July 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.