Matti Nark
Sun, Sep-08-02, 06:56
Inlammation has been associated Alzheimer's' disease and brain
aging. COX-2 inhibitors have been suggested for prevention.
The article
Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal
5-lipoxygenase in an aging brain. FASEB J. 2000
Jul;14(10):1464-9. Review. PMID: 10877840 [PubMed - indexed
for MEDLINE] http://www.fasebj.org/cgi/content/full/14/10/1464
suggests that another inflammatory enzyme from arachidonic
acid pathway, 5-lipoxygenase (5-LOX), could also have role in
brain aging, and speculates a possible role for 5-LOX
inhibitors in prevention. There is currently only one approved
5-LOX inhibitor, Zileuton, which is used to treat asthma.
However, as been mentioned here before in inflammation thread,
many natural substances are capable of inhibiting 5-LOX.
Perhaps the most selective natural 5-LOX inhibitor is
Boswellia serrata resin extract, but for example curcumin and
quercetin also inhibit 5-LOX.
Abatract of the study:
"Aging is associated with increased incidence and/or
severity of neurodegenerative pathologies. Oxygen-mediated
events are being considered as possible mechanisms
responsible for the increasing neuronal vulnerability.
Lipoxygenases are enzymes that, as cyclooxygenases (COX),
can insert oxygen into the molecule of arachidonic acid
and thereby synthesize inflammatory eicosanoids:
leukotrienes [due to 5-lipoxygenase (5-LOX) activity] and
prostaglandins (via COX activity). It appears that 5-LOX
is expressed in central nervous system neurons and may
participate in neurodegeneration. 5-LOX- triggered cell
death may be initiated by the enzymatic activity of 5-LOX
but could also occur via the nonenzymatic actions of the
5-LOX protein; new data point to the possibility that
5-LOX protein exerts actions such as interaction with
tyrosine kinase receptors, cytoskeletal proteins, and the
nucleus. The expression of neuronal 5-LOX is susceptible
to hormonal regulation, presumably due to the presence of
hormone-responsive elements in the structure of the 5-LOX
gene promoter. The expression of the 5-LOX gene and the
activity of the 5-LOX pathway are increased in elderly
subjects. One possible mechanism of such 5-LOX
up-regulation implies the contribution of aging-associated
hormonal changes: relative melatonin deficiency and/or
hyperglucocorticoidemia. Thus, the 5-LOX pathway could
become a promising target of neuroprotective therapies for
the aging brain"
An excerpt from the body of the article:
"Based on the above-described evidence indicating a role
for 5- LOX in neurodegeneration, it is becoming apparent
that drugs capable of suppressing this inflammatory
pathway might be useful in treating aging-associated
neurodegenerative diseases such as Alzheimer’s. Recent
clinical studies point to the beneficial effects of
antiinflammatory treatments in Alzheimer’s patients (56 ,
57) . The drugs considered in such studies belong
predominantly to a family of nonselective nonsteroid
antiinflammatory drugs (NSAIDs). More recently, attention
has been directed toward the development of selective
cyclooxygenase-2 (COX-2) inhibitors (58) . On the other
hand, no clinical studies have yet been reported about the
use of specific 5-LOX inhibitors in Alzheimer’s patients
or in any other neurodegenerative disease. Zileuton,
currently the only clinically available selective 5-LOX
inhibitor, is being used to treat asthma (59) . Whether
the blood–brain permeability of this drug is sufficient to
allow for its trial in neurodegenerative diseases is not
clear. If so, a pilot study of zileuton in Alzheimer’s
patients would be indicated. Moreover, based on the
evidence that 5-LOX expression differs between young and
old subjects, it is possible that the efficacy of
selective 5-LOX inhibitors in reducing 5-LOX- mediated
pathologies will be greater in elderly than in young
subjects; namely, a similar concept was recently indicated
by a study that addressed the role of the 5-LOX promoter
genotype in the response of asthma patients to treatment
with 5-LOX inhibitors (60) . Since the presence of a
naturally occurring family of DNA sequence variants in the
5-LOX gene promoter diminished promoter-reporter activity
in vitro (55) , Drazen et al. (60) suggested that patients
with such sequence variants may have diminished gene
transcription and, therefore, a diminished clinical
response to treatment with 5- LOX inhibitors. We propose
that the opposite could be the case in elderly subjects:
due to increased neuronal 5-LOX expression in aging, the
elderly could respond better than the young to treatment
with selective 5-LOX inhibitors. Future studies are needed
to fully evaluate the role of the 5-LOX pathway in the
pathobiology and treatment of aging-associated
neurodegenerative diseases."
--
Matti Narkia
aging. COX-2 inhibitors have been suggested for prevention.
The article
Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal
5-lipoxygenase in an aging brain. FASEB J. 2000
Jul;14(10):1464-9. Review. PMID: 10877840 [PubMed - indexed
for MEDLINE] http://www.fasebj.org/cgi/content/full/14/10/1464
suggests that another inflammatory enzyme from arachidonic
acid pathway, 5-lipoxygenase (5-LOX), could also have role in
brain aging, and speculates a possible role for 5-LOX
inhibitors in prevention. There is currently only one approved
5-LOX inhibitor, Zileuton, which is used to treat asthma.
However, as been mentioned here before in inflammation thread,
many natural substances are capable of inhibiting 5-LOX.
Perhaps the most selective natural 5-LOX inhibitor is
Boswellia serrata resin extract, but for example curcumin and
quercetin also inhibit 5-LOX.
Abatract of the study:
"Aging is associated with increased incidence and/or
severity of neurodegenerative pathologies. Oxygen-mediated
events are being considered as possible mechanisms
responsible for the increasing neuronal vulnerability.
Lipoxygenases are enzymes that, as cyclooxygenases (COX),
can insert oxygen into the molecule of arachidonic acid
and thereby synthesize inflammatory eicosanoids:
leukotrienes [due to 5-lipoxygenase (5-LOX) activity] and
prostaglandins (via COX activity). It appears that 5-LOX
is expressed in central nervous system neurons and may
participate in neurodegeneration. 5-LOX- triggered cell
death may be initiated by the enzymatic activity of 5-LOX
but could also occur via the nonenzymatic actions of the
5-LOX protein; new data point to the possibility that
5-LOX protein exerts actions such as interaction with
tyrosine kinase receptors, cytoskeletal proteins, and the
nucleus. The expression of neuronal 5-LOX is susceptible
to hormonal regulation, presumably due to the presence of
hormone-responsive elements in the structure of the 5-LOX
gene promoter. The expression of the 5-LOX gene and the
activity of the 5-LOX pathway are increased in elderly
subjects. One possible mechanism of such 5-LOX
up-regulation implies the contribution of aging-associated
hormonal changes: relative melatonin deficiency and/or
hyperglucocorticoidemia. Thus, the 5-LOX pathway could
become a promising target of neuroprotective therapies for
the aging brain"
An excerpt from the body of the article:
"Based on the above-described evidence indicating a role
for 5- LOX in neurodegeneration, it is becoming apparent
that drugs capable of suppressing this inflammatory
pathway might be useful in treating aging-associated
neurodegenerative diseases such as Alzheimer’s. Recent
clinical studies point to the beneficial effects of
antiinflammatory treatments in Alzheimer’s patients (56 ,
57) . The drugs considered in such studies belong
predominantly to a family of nonselective nonsteroid
antiinflammatory drugs (NSAIDs). More recently, attention
has been directed toward the development of selective
cyclooxygenase-2 (COX-2) inhibitors (58) . On the other
hand, no clinical studies have yet been reported about the
use of specific 5-LOX inhibitors in Alzheimer’s patients
or in any other neurodegenerative disease. Zileuton,
currently the only clinically available selective 5-LOX
inhibitor, is being used to treat asthma (59) . Whether
the blood–brain permeability of this drug is sufficient to
allow for its trial in neurodegenerative diseases is not
clear. If so, a pilot study of zileuton in Alzheimer’s
patients would be indicated. Moreover, based on the
evidence that 5-LOX expression differs between young and
old subjects, it is possible that the efficacy of
selective 5-LOX inhibitors in reducing 5-LOX- mediated
pathologies will be greater in elderly than in young
subjects; namely, a similar concept was recently indicated
by a study that addressed the role of the 5-LOX promoter
genotype in the response of asthma patients to treatment
with 5-LOX inhibitors (60) . Since the presence of a
naturally occurring family of DNA sequence variants in the
5-LOX gene promoter diminished promoter-reporter activity
in vitro (55) , Drazen et al. (60) suggested that patients
with such sequence variants may have diminished gene
transcription and, therefore, a diminished clinical
response to treatment with 5- LOX inhibitors. We propose
that the opposite could be the case in elderly subjects:
due to increased neuronal 5-LOX expression in aging, the
elderly could respond better than the young to treatment
with selective 5-LOX inhibitors. Future studies are needed
to fully evaluate the role of the 5-LOX pathway in the
pathobiology and treatment of aging-associated
neurodegenerative diseases."
--
Matti Narkia