Compound holds promise for neurodegenerative diseases
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Newsdesk Findings in a mouse model of Rett’s syndrome suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathogenesis of this X-linked mental-retardation disorder. This new insight into the pathogenesis of the disorder may suggest possible targets for therapeutic intervention. Rett’s syndrome (also known as RTT disease), which affects about one in 10 000–15 000 girls, causes massive deterioration in health starting at about 6 months of age. Patients can survive to adulthood with proper care, but have severe mental retardation, seizures, and ataxia. 80% of human cases are associated with a mutation in MECP2 on the X chromosome. This gene encodes a binding protein that regulates transcription of other genes. Researchers at Massachusetts Institute of Technology developed Mecp2 knock-out mice to investigate the disorder, and early studies suggested that BDNF expression was altered in these mice. In the latest study, Qiang Chang (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) and colleagues show that BDNF expression is low in Mecp2 knock-out mice (Neuron 2006; 49: 341–48). When the researchers completely knocked out the Bdnf gene in Mecp2 knock-out mice, the mice developed symptoms earlier. Further- more, when BDNF was overexpressed, symptoms of the disorder in mice were ameliorated. “This is the first instance that the Rett disease progression has been altered by changing expression of another gene”, says reseacher Rudolf Jaenisch in a press release issued by the Rett Syndrome Research Foundation. “Our results suggest therapeutic opportunites through the manip- ulation of BDNF expression”, state the authors. “This paper is very interesting”, says Michael Johnston (Kennedy Krieger Institute at Johns Hopkins University School of Medicine, Baltimore, USA), “in that it links BDNF with the pathogenesis of Rett’s syndrome in these mice.” However, there are several differences between the disorder in mice and Rett’s syndrome in girls. The mice seem to have lower neuronal activity, but in girls, hyperventilation, seizures, abnormal electroencephalograms, and hyper- kinetic hand movements point to increased neuronal activity. “Although Bdnf is one of many genes regulated by Mecp2, it is the first one shown to modulate disease progression. Future studies will be aimed at understanding its effect on the course of RTT disease”, the authors conclude. Peter Hayward 210 http://neurology.thelancet.com Vol 5 March 2006 Neurotrophic factor linked to Rett’s syndrome A compound specifically targeted to suppress brain-cell inflammation and neuron loss associated with Alzheimer’s disease (AD) has shown promising preliminary results. “We have developed a novel class of orally bioavailable, CNS-penetrating, small molecule compounds that selectively suppress proinflammatory cytokine upregulation in the brain, leading to attenuation of AD-relevant pathophysiology progression”, says study author Martin Watterson (Northwestern University, Chicago, IL, USA). These findings are part of a rapid rise in evidence implicating unregulated neuroinflammation in disease pro- gression; targeting key signalling pathways associated with proinflam- matory cytokine production could lead to the development of safe and selective therapies for AD and related neurodegenerative diseases. In mouse models of AD, researchers gave MW01-5-188WH orally on a daily basis. In a series of experiments, they assessed several attributes of the substance including suppression of CNS versus peripheral inflammation, liver toxicity, and in-vivo efficacy. MW01-5-188WH suppressed human amyloid--induced glia activation and neuroinflammation, which was associated with the restoration of synaptic dysfunction markers in the hippocampus to baseline levels. Treatment also attenuated behavioural deficits (J Neurosci 2006; 26: 662–70). The compound selectively inhibited CNS inflammation, but did not suppress peripheral inflammation over similar dose ranges and time windows. This finding has important implications, explains Watterson, because this kind of drug would be less likely to suppress peripheral immunity. “Our results, in the context of previous publications, suggest that such therapies could be started coincident with the appearance of clinical signs of cognitive function changes, the current clinical gold standard in diagnosis of age-onset Alzheimer’s”, says Watterson. “Most studies to date have approached the anti-inflammatory hypothesis of Alzheimer’s disease in a blanket fashion and this has probably contributed to some of the confusing reports that have appeared in the literature”, comments Claire Shepherd (Prince of Wales Medical Research Institute, Sydney, Australia). “This study demonstrates possible therapeutic benefits from fine-tuning the inflammatory response to regain its homeostatic control, but represents early findings.” Roxanne Nelson Compound holds promise for neurodegenerative diseases
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Transcript of Compound holds promise for neurodegenerative diseases
Newsdesk
Findings in a mouse model of Rett’ssyndrome suggest that brain-derivedneurotrophic factor (BDNF) is involvedin the pathogenesis of this X-linkedmental-retardation disorder. This newinsight into the pathogenesis of thedisorder may suggest possible targetsfor therapeutic intervention.
Rett’s syndrome (also known as RTTdisease), which affects about one in10 000–15 000 girls, causes massivedeterioration in health starting atabout 6 months of age. Patients cansurvive to adulthood with proper care,but have severe mental retardation,seizures, and ataxia. 80% of humancases are associated with a mutation inMECP2 on the X chromosome. Thisgene encodes a binding protein thatregulates transcription of other genes.
Researchers at MassachusettsInstitute of Technology developedMecp2 knock-out mice to investigatethe disorder, and early studies
suggested that BDNF expression wasaltered in these mice. In the lateststudy, Qiang Chang (WhiteheadInstitute for Biomedical Research,Cambridge, MA, USA) and colleaguesshow that BDNF expression is low inMecp2 knock-out mice (Neuron 2006;49: 341–48). When the researcherscompletely knocked out the Bdnf genein Mecp2 knock-out mice, the micedeveloped symptoms earlier. Further-more, when BDNF was overexpressed,symptoms of the disorder in mice wereameliorated.
“This is the first instance that theRett disease progression has beenaltered by changing expression ofanother gene”, says reseacher RudolfJaenisch in a press release issued by theRett Syndrome Research Foundation.“Our results suggest therapeuticopportunites through the manip-ulation of BDNF expression”, state theauthors.
“This paper is very interesting”, saysMichael Johnston (Kennedy KriegerInstitute at Johns Hopkins UniversitySchool of Medicine, Baltimore, USA),“in that it links BDNF with thepathogenesis of Rett’s syndrome inthese mice.” However, there areseveral differences between thedisorder in mice and Rett’s syndromein girls. The mice seem to have lowerneuronal activity, but in girls,hyperventilation, seizures, abnormalelectroencephalograms, and hyper-kinetic hand movements point toincreased neuronal activity.
“Although Bdnf is one of manygenes regulated by Mecp2, it is thefirst one shown to modulate diseaseprogression. Future studies will beaimed at understanding its effect onthe course of RTT disease”, theauthors conclude.
Peter Hayward
210 http://neurology.thelancet.com Vol 5 March 2006
Neurotrophic factor linked to Rett’s syndrome
A compound specifically targeted tosuppress brain-cell inflammationand neuron loss associated withAlzheimer’s disease (AD) has shownpromising preliminary results.
“We have developed a novel class oforally bioavailable, CNS-penetrating,small molecule compounds thatselectively suppress proinflammatorycytokine upregulation in the brain,leading to attenuation of AD-relevantpathophysiology progression”, saysstudy author Martin Watterson(Northwestern University, Chicago, IL,USA).
These findings are part of a rapid risein evidence implicating unregulatedneuroinflammation in disease pro-gression; targeting key signallingpathways associated with proinflam-matory cytokine production couldlead to the development of safe andselective therapies for AD and relatedneurodegenerative diseases.
In mouse models of AD, researchersgave MW01-5-188WH orally on a dailybasis. In a series of experiments, theyassessed several attributes of thesubstance including suppression ofCNS versus peripheral inflammation,liver toxicity, and in-vivo efficacy.MW01-5-188WH suppressed humanamyloid-�-induced glia activationand neuroinflammation, which wasassociated with the restoration ofsynaptic dysfunction markers inthe hippocampus to baseline levels.Treatment also attenuated behaviouraldeficits (J Neurosci 2006; 26: 662–70).
The compound selectively inhibitedCNS inflammation, but did notsuppress peripheral inflammationover similar dose ranges and timewindows. This finding has importantimplications, explains Watterson,because this kind of drug would beless likely to suppress peripheralimmunity.
“Our results, in the context ofprevious publications, suggest thatsuch therapies could be startedcoincident with the appearance ofclinical signs of cognitive functionchanges, the current clinical goldstandard in diagnosis of age-onsetAlzheimer’s”, says Watterson.
“Most studies to date haveapproached the anti-inflammatoryhypothesis of Alzheimer’s disease in ablanket fashion and this has probablycontributed to some of the confusingreports that have appeared in theliterature”, comments Claire Shepherd(Prince of Wales Medical ResearchInstitute, Sydney, Australia). “Thisstudy demonstrates possibletherapeutic benefits from fine-tuningthe inflammatory response to regainits homeostatic control, butrepresents early findings.”
Roxanne Nelson
Compound holds promise for neurodegenerative diseases
