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Protective effect of
L-deprenyl against apoptosis induced by okadaic acid in
cultured neuronal cells.
Suuronen T, Kolehmainen P, Salminen A Department of
Neuroscience and Neurology, University of Kuopio, P.O. Box
1627, FIN-70211, Kuopio, Finland.
Biochem Pharmacol 2000 Jun 15;59(12):1589-95
L-Deprenyl, an irreversible MAO-B (monoamine oxidase B,
EC 1.4.3.4) inhibitor, is used for the treatment of
Parkinson's disease and to delay the progression of
Alzheimer's disease. L-Deprenyl also exhibits protective
effects against neuronal apoptosis which are independent of
its ability to inhibit MAO-B. The purpose of this study was
to compare the antiapoptotic efficacy of L-deprenyl against
different types of apoptotic inducers in three neuronal
cell culture models. The level of apoptosis was quantified
by measuring the activation of caspase-3 enzyme, which is
the main apoptotic executioner in neuronal cells. MTT
[3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium
bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27)
assays were used to demonstrate the cytotoxic response of
apoptotic treatments. Our results showed that okadaic acid,
an inhibitor of protein phosphatase 1 and 2A, induced a
prominent increase in caspase-3 activity both in cultured
hippocampal and cerebellar granule neurons as well as in
Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl
offered a significant protection against the apoptotic
response induced by okadaic acid in all three neuronal
models. The best protection appeared at the concentration
level of 10(-9) M. L-Deprenyl also provided a protection
against apoptosis after AraC (cytosine beta-D-arabinoside)
treatment in hippocampal neurons and Neuro-2a cells and
after etoposide treatment in Neuro-2a cells. However,
L-deprenyl did not offer any protection against apoptosis
caused by serum withdrawal or potassium deprivation.
Okadaic acid treatment in vivo is known to induce an
Alzheimer's type of hyperphosphorylation of tau protein,
formation of beta-amyloid plaques, and a severe memory
impairment. Our results show that the okadaic acid model
provides a promising tool to study the molecular basis of
Alzheimer's disease and to screen the neuroprotective
capacity of L-deprenyl derivatives.
Vitamin E for Alzheimer's
disease.
Tabet N, Birks J, Grimley Evans J. Old Age Psychiatry,
The Maudsley Hospital, Denmark Hill, London, UK, SE5 8AZ.
N.Tabet@iop.kcl.ac.uk
Cochrane Database Syst Rev 2000;(4):CD002854
BACKGROUND: Vitamin E is a dietary compound that
functions as an antioxidant scavenging toxic free radicals.
Evidence that free radicals may contribute to the
pathological processes in Alzheimer's disease has led to
interest in the use of vitamin E in the treatment of this
disorder.
OBJECTIVES: To examine the effects of vitamin E
treatment for people with Alzheimer's disease.
EARCH STRATEGY: The Cochrane Dementia Group Register of
Clinical Trials was searched with the following terms:
vitamin E, Alzheimer's disease, dementia, alpha-tocopherol,
cognitive impairment, cognitive function and controlled
trials. The latest search was carried out in July 2000.
SELECTION CRITERIA: All unconfounded, double blind,
randomized trials in which treatment with vitamin E at any
dose was compared with placebo for patients with
Alzheimer's disease.
DATA COLLECTION AND ANALYSIS: Two reviewers
independently applied the selection criteria an assessed
study quality. One reviewer extracted and analysed the
data. For each outcome measure data were sought on every
patient randomized. Where such data were not available an
analysis of patients who completed treatment was
conducted.
MAIN RESULTS: Only one study was identified which met
the inclusion criteria (Sano 1997). The primary outcome
used in this study of 341 participants was survival time to
the first of 4 endpoints, death, institutionalisation, loss
of 2 out of 3 basic activities of daily living, or severe
dementia, defined as a global Clinical Dementia Rating of
3. The investigators reported the total numbers in each
group who reached the primary endpoint within two years for
participants completing the study ("completers"). There
appeared to be some benefit from vitamin E with fewer
participants reaching endpoint - 58% (45/77) of completers
compared with 74% (58/78) - a Peto odds ratio of 0.49, 95%
confidence interval 0.25 to 0.96. However, more
participants taking vitamin E suffered a fall (12/77
compared with 4/78; odds ratio 3.07, 95% CI 1.09 to 8.62).
It was not possible to interpret the reported results for
specific endpoints or for secondary outcomes of cognition,
dependence, behavioural disturbance and activities of daily
living.
REVIEWER'S CONCLUSIONS: There is insufficient evidence
of efficacy of vitamin E in the treatment of people with
with Alzheimer's disease. The one published trial of
acceptable methodology (Sano 1997) was restricted to
patients with moderate disease, and the published results
are difficult to interpret. There is sufficient evidence of
possible benefit to justify further studies. There was an
excess of falls in the vitamin E group compared with
placebo which requires further evaluation.
Huperzine A
(shuangyiping): a promising drug for Alzheimer's
disease.
Tang XC. Department of Pharmacology, State Key
Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, China.
Zhongguo Yao Li Xue Bao 1996 Nov;17(6):481-4
Hup A, a novel alkaloid isolated from Chineses herb
Huperzia serrata, is a potent and selective inhibitor of
AChE, with a rapid absorption and penetration into the
brain in experimental animals. The inhibition is reversible
with a longer duration of action. Hup A exhibited
memory-enhancing activities in a broad range of animal
cognitive model. Compared to Phy, Tac, and Gal, Hup A has
better therapeutic indices, and peripheral cholinergic side
effects are minimal at therapeutic doses. These findings
suggest that Hup A is a promising candidate for clinical
development as a symptomatic treatment for AD.
[Cognitive enhancement
effect of piracetam in patients with mild cognitive
impairment and dementia]. [Article in
Hungarian]
Tariska P, Paksy A Memoria Klinika, Orszagos
Pszichiatriai es Neurologiai Intezet, Budapest.
Orv Hetil 2000 May 28;141(22):1189-93
Effectiveness and tolerability of two
piracetam-containing drugs were compared in the frame of an
open, multicentre, Phase-IV, prospective study with group
and self control carried out in 9 Hungarian centres in
1998. Patients with cognitive decline from Alzheimer's
disease and/or cerebrovascular origin have received the
drug, in the first 4 weeks in 4800, later 2400 mg daily
doses. One hundred four patients finished the study. No
relevant difference with statistically significant degree
was registered between the two groups. Based on this fact
in this study data of the 104 patients were examined
together. Authors examined two problems. The first: on
which cognitive function is more effective the drug. Five
factors of the modified Mini-Mental State Examination were
separated and compared. Nearly all of them significantly
increased especially the factors of memory, and
concentration-psychomotor speed. The second examined field:
are there certain subgroups with prognostic value about the
effectiveness of piracetam treatment. Neither the duration
of the illness, nor etiologic diagnosis, severity of
cognitive decline, or former treatment with piracetam did
influence significantly the efficacy. In case of depressive
symptoms such connection was established: the more
pronounced the severity of these symptoms the higher
improvement can be expected in cognitive functions. This
was also stressed by the logistic regression analysis.
Authors described an original evaluation method of the
trail-making test, which could widen the application of
this popular test in psychopharmacologic studies. Final
conclusions: the cognitive enhancer effect of piracetam
appeared in a few weeks. This treatment could be effective
even in Alzheimer's disease, in case of more pronounced
cognitive decline, longer duration of the illness, and in
case of former piracetam treatment as well. The degree of
cognitive improvement was most pronounced in patients with
comorbid depressive symptoms.
A 1-year controlled trial
of acetyl-l-carnitine in early-onset AD.
Thal LJ, Calvani M, Amato A, Carta A. Department of
Neurosciences, University of California-San Diego School of
Medicine, La Jolla, CA 92093-0624, USA. lthal@ucsd.edu
Neurology 2000 Sep 26;55(6):805-10
OBJECTIVE: To determine the efficacy of
acetyl-l-carnitine (ALCAR) on the rate of decline in
early-onset AD patients.
METHODS: A 1-year, multicenter, double-blind,
placebo-controlled, randomized trial was conducted.
Subjects were 45 to 65 years old, with a diagnosis of
probable AD according to National Institute of Neurological
Communicative Disorders-Alzheimer's Disease and Related
Disorders Association criteria and had a Mini-Mental State
Examination (MMSE) score between 12 and 26. They were
treated with ALCAR (1 g tid) or placebo. Primary outcome
measures were the Alzheimer's Disease Assessment
Scale-Cognitive Component and the Clinical Dementia Rating
Scale. Secondary measures included the ADAS Non-Cognitive
Subscale, the MMSE, an Activities of Daily Living Scale
(ADL), and a Clinician-Based Impression of Change
(CIBIC).
RESULTS: Two-hundred twenty-nine patients were enrolled
and randomized to drug treatment, with 117 taking placebo
and 112 taking ALCAR. There were no significant differences
between the two groups at baseline. For the primary outcome
measures, there were no significant differences between the
treatment groups on the change from baseline to endpoint in
the intent-to-treat analysis. In the completer sample only,
there was less deterioration in the MMSE for the
ALCAR-treated subjects. There was no difference in rate of
decline on the CIBIC and the ADL scale. There were no
significant differences in the incidence of adverse events
by treatment arm.
CONCLUSION: Overall, in a prospectively performed study
in young-onset AD patients, ALCAR failed to slow decline.
Less decline was seen on the MMSE in the completer sample
only, with the difference being mediated by reducing
decline in attention. A combination of ALCAR and a
cholinesterase inhibitor should be tested for
additivity.
Oral physostigmine and
lecithin improve memory in Alzheimer disease.
Thal LJ, Fuld PA, Masur DM, Sharpless NS.
Ann Neurol 1983 May;13(5):491-6
Eight patients with early Alzheimer disease were treated
with gradually increasing multiple daily doses of oral
physostigmine and supplemental lecithin. Six individuals
showed improvement in total recall and retrieval from
long-term storage (LTR), with a decrease in intrusions (a
measure of inaccurate recall). The optimal individual dose
was either 2.0 or 2.5 mg of physostigmine for each
responding patient. Results of this open trial were
subsequently replicated during a double-blind crossover
trial comparing physostigmine treatment to placebo. All six
patients again demonstrated improvement in total recall and
LTR, with a decrease in intrusions. The decrease in
intrusions was strongly correlated with increasing
inhibition of cholinesterase activity in cerebrospinal
fluid, suggesting that the degree of improvement in the
patient's memory was related to the amount of physostigmine
that reached the brain. Other neurotransmitters and
metabolites in cerebrospinal fluid were unaffected by the
physostigmine therapy, suggesting a specific effect of
physostigmine on the cholinergic system. The results
suggest that small oral doses of physostigmine combined
with lecithin ingestion have therapeutic benefit for some
patients with Alzheimer disease.
Monoamine oxidase-B
inhibitors in the treatment of Alzheimer's
disease.
Thomas T Woodlands Medical and Research Center, 3150
Tampa Road, Oldsmar, FL 34677, USA.
tthomas@tampabay.rr.com
Neurobiol Aging 2000 Mar-Apr;21(2):343-8
The monoamine oxidase-B (MAO-B) inhibitor L-deprenyl
(Selegiline) is effective in treating Parkinson's disease
and possibly Alzheimer's disease, with a concomitant
extension of life span. It has been suggested that the
therapeutic efficacy of L-deprenyl may involve actions
other than the inhibition of the enzyme MAO-B. This article
reviews some novel actions of L-deprenyl and suggests that
stimulation of nitric oxide (NO) production could be
central to the action of the drug. L-Deprenyl induced rapid
increases in NO production in brain tissue and cerebral
blood vessels. In vitro or in vivo application of
L-deprenyl produced vasodilatation. The drug also protected
the vascular endothelium from the toxic effects of
amyloid-beta peptide. Because NO modulates activities
including cerebral blood flow and memory, and reduced NO
production has been observed in AD brain, stimulation of NO
production by L-deprenyl could contribute to the
enhancement of cognitive function in AD. MAO-B inhibitors
are unique in that they exert protective effects on both
vascular and neuronal tissue and thus warrant further
consideration in the treatment of vascular and
neurodegenerative diseases associated with aging.
[New hypothesis on
etiopathogenesis of Alzheimer syndrome. Advanced glycation
end products (AGEs)] [Article in German]
Thome J, Kornhuber J, Munch G, Schinzel R, Taneli Y,
Zielke B, Rosler M, Riederer P. Psychiatrische Klinik und
Poliklinik, Universitats-Nervenklinik, Wurzburg.
Nervenarzt 1996 Nov;67(11):924-9
Despite intense efforts, it has not yet been possible to
clarify the etiopathogenesis of Alzheimer's dementia. There
are, however, hypotheses which focus on certain aspects of
this type of dementia, characterized by particular
neuropathological alterations and clinical correlates.
Recently, evidence has accumulated that advanced glycation
endproducts (AGEs) could play an important role in the
etiology of the Alzheimer's syndrome. AGEs are generated by
an irreversible reaction through the non-enzymatic,
long-term glycosylation of proteins. They are strongly
resistant to proteolytic processes and induce protein
crosslinking. They could thus inhibit the physiological
functions of many proteins. Moreover, it is suggested that
they contribute to the transformation of the soluble form
of beta-amyloid into its unsoluble version. AGEs are also
demonstrable in neurofibrillary tangles (NFTs). A further
mechanism by which AGEs might be pathogenic is via their
induction of oxidative stress. AGEs probably exert their
pathological effects not only directly because of their
chemical properties, but also by indirect receptor-mediated
mechanisms. Further investigation of AGE-mediated
mechanisms should reveal their role in the etiopathogenesis
of the Alzheimer's syndrome and, finally, lead to the
development of new pharmacological strategies aimed at
inhibiting protein cross-linking.
Interactions between
carnosine and zinc and copper: implications for
neuromodulation and neuroprotection.
Trombley PQ, Horning MS, Blakemore LJ. Biomedical
Research Facility, Department of Biological Science,
Florida State University, Tallahassee, Florida 32306-4340,
USA. trombley@neuro.fsu.edu.
Biochemistry (Mosc) 2000 Jul;65(7):807-16
This review examines interactions in the mammalian
central nervous system (CNS) between carnosine and the
endogenous transition metals zinc and copper. Although the
relationship between these substances may be applicable to
other brain regions, the focus is on the olfactory system
where these substances may have special significance.
Carnosine is not only highly concentrated in the olfactory
system, but it is also contained in neurons (in contrast to
glia cells in most of the brain) and has many features of a
neurotransmitter. Whereas the function of carnosine in the
CNS is not well understood, we review evidence that
suggests that it may act as both a neuromodulator and a
neuroprotective agent. Although zinc and/or copper are
found in many neuronal pathways in the brain, the
concentrations of zinc and copper in the olfactory bulb
(the target of afferent input from sensory neurons in the
nose) are among the highest in the CNS. Included in the
multitude of physiological roles that zinc and copper play
in the CNS is modulation of neuronal excitability. However,
zinc and copper also have been implicated in a variety of
neurologic conditions including Alzheimer's disease,
Parkinson's disease, stroke, and seizures. Here we review
the modulatory effects that carnosine can have on zinc and
copper's abilities to influence neuronal excitability and
to exert neurotoxic effects in the olfactory system. Other
aspects of carnosine in the CNS are reviewed elsewhere in
this issue.
Vitamin E
supplementation prevents spatial learning deficits and
dendritic alterations in aged apolipoprotein E-deficient
mice.
Veinbergs I, Mallory M, Sagara Y, Masliah E. Departments
of Neurosciences and Pathology, University of California,
San Diego, School of Medicine, La Jolla, California
92093-0624, USA.
Eur J Neurosci 2000 Dec;12(12):4541-6
Recent studies have suggested that altered function of
apolipoprotein E might lead to Alzheimer's disease via
oxidative stress. In this context, the objective of this
study was to determine if antioxidative treatment with
vitamin E was neuroprotective in apolipoprotein E-deficient
mice. For this purpose, 1-month-old control and
apolipoprotein E-deficient mice received dietary vitamin E
for 12 months. We showed that, compared to apolipoprotein
E-deficient mice who received a regular diet, mice treated
with vitamin E displayed a significantly improved
behavioural performance in the Morris water maze. This
improved performance was associated with preservation of
the dendritic structure in vitamin E-treated apolipoprotein
E-deficient mice. In addition, whilst untreated
apolipoprotein E-deficient mice displayed increased levels
of lipid peroxidation and glutathione, vitamin E-treated
mice showed near normal levels of both lipid peroxidation
and glutathione. These results support the contention that
vitamin E prevents the age-related neurodegenerative
alterations in apolipoprotein E-deficient mice.
The action of
acetyl-L-carnitine on the neurotoxicity evoked by amyloid
fragments and peroxide on primary rat cortical
neurones.
Virmani MA, Caso V, Spadoni A, Rossi S, Russo F, Gaetani
F. Research & Development Department, Sigma-tau
HealthScience s.p.a., Via Treviso 4, 00040 Pomezia, Italy.
ashraf.virmani@sigma-tau.it
Ann N Y Acad Sci 2001 Jun;939:162-78
The amyloid beta-peptides have been implicated in the
excitotoxic mechanism of neuronal injury in the
pathogenesis of Alzheimer's disease. In this paper we
examine the effect of different amyloid fragments (beta
A1-40, A1-28, and A25-35), as well as potential
neuroprotective compounds on rat cortical neuron viability.
Exposure of neurones to beta A25-35 or A1-40 at
concentrations as low as 1 microgram/ml inhibited,
significantly, the MTT response and this level of
inhibition was similar after 24-h or three-day exposure.
Furthermore, the level of inhibition was not affected by
the presence or absence of 5% horse serum in the medium.
Preexposure (10 min) of neurones to ALC at concentrations
of 0.1, 1, 5, and 10 mM attenuated the inhibition of the
MTT response caused by beta A25-35 (50 micrograms/ml) in
serum free medium for 24 h. The treatment of cells with
vitamin E (100 microM), catalase (4 mg/ml), NGF (0.1 and 10
ng/ml), or cycloheximide (0.1 microgram/ml) significantly
restored the MTT response that was inhibited by beta
A25-35. The mechanism for the protective actions of these
compounds against beta A25-35 toxicity is not clear but may
involve free radical scavenger action and preservation of
energy production, although other mechanisms, especially
for ALC, such as a direct effect on A-beta interaction with
charged anionic phospholipids and/or stabilizing action on
membranes, are also possible.
Vitamin B(12) and
folate in relation to the development of Alzheimer's
disease.
Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B,
Fratiglioni L. Stockholm Gerontology Research Center and
Division of Geriatric Medicine, NEUROTEC, Karolinska
Institutet, Stockholm. Huixin.wang@phs.ki.se
Neurology 2001 May 8;56(9):1188-94
OBJECTIVE: To explore the associations of low serum
levels of vitamin B(12) and folate with AD occurrence.
METHODS: A population-based longitudinal study in
Sweden, the Kungsholmen
PROJECT: A random sample of 370 nondemented persons,
aged 75 years and older and not treated with B(12) and
folate, was followed for 3 years to detect incident AD
cases. Two cut-off points were used to define low levels of
vitamin B(12) (< or =150 and < or =250 pmol/L) and
folate (< or =10 and < or =12 nmol/L), and all
analyses were performed using both definitions. AD and
other types of dementia were diagnosed by specialists
according to DSM-III-R criteria.
RESULTS: When using B(12) < or =150 pmol/L and folate
< or =10 nmol/L to define low levels, compared with
people with normal levels of both vitamins, subjects with
low levels of B(12) or folate had twice higher risks of
developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to
3.5). These associations were even stronger in subjects
with good baseline cognition (RR = 3.1, 95% CI = 1.1 to
8.4). Similar relative risks of AD were found in subjects
with low levels of B(12) or folate and among those with
both vitamins at low levels. A comparable pattern was
detected when low vitamin levels were defined as B(12) <
or =250 pmol/L and folate < or =12 nmol/L.
CONCLUSIONS: This study suggests that vitamin B(12) and
folate may be involved in the development of AD. A clear
association was detected only when both vitamins were taken
into account, especially among the cognitively intact
subjects. No interaction was found between the two
vitamins. Monitoring serum B(12) and folate concentration
in the elderly may be relevant for prevention of AD.
Huperzine A improves
cognitive deficits caused by chronic cerebral hypoperfusion
in rats.
Wang LM, Han YF, Tang XC. State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 200031, Shanghai, People's Republic of
China.
Eur J Pharmacol 2000 Jun 9;398(1):65-72
The effects of (-)-huperzine A, a promising therapeutic
agent for Alzheimer's disease, on learning behavior and on
alterations of the cholinergic system, the oxygen free
radicals and energy metabolites induced by permanent
bilateral ligation of the common carotid arteries were
investigated in rats. Daily oral administration of
huperzine A produced a significant improvement of the
deficit in the learning of the water maze task, beginning
28 days after ischemia, correlating to about 33-40%
inhibition of acetylcholinesterase activity in cortex and
hippocampus. Huperzine A significantly restored the
decrease in choline acetyltransferase activity in
hippocampus and significantly reduced the increases in
superoxide dismutase, lipid peroxide, lactate and glucose
to their normal levels. The present findings demonstrate
that the improvement by huperzine A of the cognitive
dysfunction in the late phase in chronically hypoperfused
rats is due to its effects, not only on the cholinergic
system, but also on the oxygen free radical system and
energy metabolism. Our results strongly suggest that
huperzine A has therapeutic potential for the treatment of
dementia caused by cholinergic dysfunction and/or decrease
of cerebral blood flow.
Functional imaging of
the frontal lobes in organic dementia. Regional cerebral
blood flow findings in normals, in patients with
frontotemporal dementia and in patients with Alzheimer's
disease, performing a word fluency test.
Warkentin S, Passant U. Department of Psychogeriatrics,
University Hospital, Lund, Sweden.
Dement Geriatr Cogn Disord 1997 Mar-Apr;8(2):105-9
Patterns of functional cortical activation were studied
by means of regional cerebral blood flow measurements,
performed during rest and during a word fluency task in
normal subjects (n = 22), in patients with Alzheimer's
disease (n = 17), and in patients with frontotemporal
dementia (n = 15). Although all groups showed a significant
activation of the Broca's area during word production, the
activation of the dorsolateral prefrontal cortex was
clearly subnormal in both dementia groups. The frontal
dysfunction was not explained by number of words produced,
illness duration, or age. Thus, the results demonstrate
that the word fluency task is a sensitive measure of
frontal lobe function, and its incorporation in imaging
studies may facilitate the detection of subtle functional
impairment of the frontal lobes in organic dementia.
A controlled study of 2
doses of idebenone in the treatment of Alzheimer's
disease.
Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann
WM. Institute of Psychology, Johann Wolfgang Goethe
University, Frankfurt/Main, Germany.
Neuropsychobiology 1997;36(2):73-82
Two doses of idebenone were studied in a prospective,
randomized, double-blind, placebo-controlled multicentre
study in patients suffering from dementia of the Alzheimer
type (DAT) of mild to moderate degree. Diagnosis was based
on DSM-III-R (primary degenerative dementia) and
NINCDS-ADRDA criteria (probable Alzheimer's disease). A
total of 300 patients were randomized to either placebo,
idebenone 30 mg t.i.d. or 90 mg t.i.d. (n = 100, each) and
treated for 6 months. The primary outcome measure was the
total score of the Alzheimer's Disease Assessment Scale
(ADAS-Total) at month 6. Secondary outcome measures were
the ADAS cognitive (ADAS-Cog) and noncognitive scores
(ADAS-Noncog), the clinical global response
(CGI-Improvement), the MMSE, the Digit Symbol Substitution
test (DSS) and several scales for the assessment of daily
activities (the self- and observer-rating scales NAA and
NAB of the Nuremberg Age Inventory NAI and Greene's
Assessment). Safety parameters were adverse events, vital
signs, ECG and clinical laboratory parameters. Clinical and
psychometric evaluations were performed at baseline, and
after 1, 3 and 6 months of treatment. After month 6
idebenone 90 mg t.i.d. showed statistically significant
improvement in the primary efficacy variable ADAS-Total and
in ADAS-Cog. An analysis of therapy responders performed
for 3 outcome measures (CGI-global improvement, ADAS-Cog,
ADAS-Noncog), selected to represent different domains of
assessment, revealed significant superiority of idebenone
90 mg t.i.d. with respect to placebo in each of the 3
variables and in the concordance of responses across the 3
measures. Exploratory results for a subgroup of patients
(ADAS-Total > or = 20) showed dose-related superiority
of idebenone additionally on ADAS-Noncog and the
CGI-Improvement scale. Safety results were inconspicuous
for all assessments. The study results demonstrate the
efficacy and safety of idebenone in the treatment of DAT
patients.
Tryptophan degradation
and immune activation in Alzheimer's disease.
Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs
D. Institute of Medical Chemistry and Biochemistry,
University of Innsbruck, Austria.
J Neural Transm 2000;107(3):343-53
Alzheimer's disease (AD) is likely associated with
systemic immune activation. During immune response,
interferon-gamma stimulates indoleamine 2,3-dioxygenase
(IDO) converting tryptophan to N-formylkynurenine followed
by kynurenine in an ensuing step. Thus, IDO activity is
estimated by the kynurenine per tryptophan quotient
(Kyn/Trp). In 21 patients suffering from AD, in 20 controls
of similar age, and in 49 blood donors we measured serum
tryptophan and kynurenine concentrations by HPLC. Lower
tryptophan concentrations were found in elderly control
subjects compared to blood donors (62.1 vs. 73.0 microM, p
< 0.005). Tryptophan concentrations tended to be still
lower in AD patients (54.4 microM, p = 0.07) compared to
elderly controls. Enhanced tryptophan degradation in
patients was reflected by significantly increased Kyn/Trp
(46.1 vs. 34.1 in elderly controls, p < 0.05).
Correlations were found in patients between Kyn/Trp and
concentrations of soluble immune markers in serum, i.e.,
neopterin, interleukin-2 receptor and tumor necrosis factor
receptor (all p < 0.001). Increased Kyn/Trp was
associated with reduced cognitive performance. Tryptophan
degradation due to immune activation may exert impact on
the pathogenesis of AD.
Memantine in severe
dementia: results of the 9M-Best Study (Benefit and
efficacy in severely demented patients during treatment
with memantine).
Winblad B, Poritis N. Karolinska Institutet, Department
of Clinical Neuroscience and Family Medicine, Huddinge
University Hospital, Sweden.
Int J Geriatr Psychiatry 1999 Feb;14(2):135-46
OBJECTIVES: To assess clinical efficacy and safety of
memantine--an uncompetitive N-methyl-D-aspartate (NMDA)
antagonist--in moderately severe to severe primary
dementia.
MATERIALS AND METHODS: Dementia was defined by DSM-III-R
criteria and severity was assessed by the Global
Deterioration Scale (stages 5-7) and the Mini-Mental State
Examination (< 10 points). Primary endpoints were the
Clinical Global Impression of Change (CGI-C) rated by the
physician, and the Behavioural Rating Scale for Geriatric
Patients (BGP), subscore 'care dependence', rated by the
nursing staff. Secondary endpoints included the modified
D-Scale (Arnold/Ferm).
RESULTS: The ITT sample comprised 166 patients and 151
patients were treated per protocol. At 12-week ITT endpoint
analysis, 82 received memantine 10 mg per day, 84 placebo.
Dementia was in 49% of the Alzheimer type and in 51% of the
vascular type (CT, Hachinski score). A positive response in
the CGI-C was seen in 73% versus 45% in favour of memantine
(stratified Wilcoxon p < 0.001), independent of the
etiology of dementia. The results in the BGP subscore 'care
dependence' were 3.1 points improvement under memantine and
1.1 points under placebo (p = 0.016). A coincident response
of the two independent target variables was observed in
61.3% (memantine) versus 31.6% (placebo). Secondary
endpoint analysis of the D-Scale assessing basic ADL
functions support the primary results. Regarding the safety
profile, no significant differences between treatment
groups were observed.
CONCLUSIONS: The results of this trial support the
hypothesis that memantine treatment leads to functional
improvement and reduces care dependence in severely
demented patients.
Aluminium and
Alzheimer's disease.
Wisniewski HM, Wen GY. New York State Institute for
Basic Research in Developmental Disabilities, Staten Island
10314.
Ciba Found Symp 1992;169:142-54; discussion 154-64
The hypothesis that aluminium (Al) is a cause of (or a
risk factor in) the development of beta-amyloid plaques and
neurofibrillary tangles (NFT) and dementia in Alzheimer's
disease (AD) is based on studies by Wisniewski et al,
Klatzo et al and Terry & Pena in 1965 that showed that
injection of experimental animals with Al compounds induces
the formation of NFT. Other publications revealed that Al
affects cognitive functions in experimental animals and
humans undergoing dialysis for renal failure. Electron
probe and laser microprobe mass analysis (LAMMA) studies
have demonstrated the presence of Al in NFT and cores of
amyloid stars and nuclei of neurons in AD patients. Other
studies have indicated the association between amyotrophic
lateral sclerosis/Guam parkinsonism-dementia complex and Al
in the environment. A recent report suggests that the
chelating agent desferrioxamine slows the rate of cognitive
decline in AD patients. Extensive studies of the pathology
of AD and Al-induced encephalopathy by our group and others
indicate that Al does not cause Alzheimer's disease
neuropathology. However, under certain conditions,
cognition can be affected when Al enters the brain.
Therefore, for individuals with renal failure or undergoing
dialysis or individuals with a damaged blood-brain barrier,
the intake of Al should be controlled.
The efficacy of ginkgo
for elderly people with dementia and age-associated memory
impairment: new results of a randomized clinical
trial
van Dongen MC, van Rossum E, Kessels AG, Sielhorst HJ,
Knipschild PG Department of Epidemiology, Maastricht
University, The Netherlands. [Record supplied by
publisher]
J Am Geriatr Soc 2000 Oct;48(10):1183-94
OBJECTIVES: To evaluate the efficacy, the
dose-dependence, and the durability of the effect of the
ginkgo biloba special extract EGb 761 (ginkgo) in older
people with dementia or age-associated memory
impairment.
DESIGN: A 24-week, randomized, double-blind,
placebo-controlled, parallel-group, multicenter trial.
SETTING: Homes for the elderly in the southern part of
the Netherlands.
PARTICIPANTS: Older persons with dementia (either
Alzheimer's dementia or vascular dementia; mild to moderate
degree) or age-associated memory impairment (AAMI). 214
Participants were recruited from 39 homes for the
elderly.
INTERVENTION: The participants were allocated randomly
to treatment with EGb 761 (2 tablets per day, total dosage
either 240 (high dose) or 160 (usual dose) mg/day) or
placebo (0 mg/d). The total intervention period was 24
weeks. After 12 weeks of treatment, the initial ginkgo
users were randomized once again to either continued ginkgo
treatment or placebo treatment. Initial placebo use was
prolonged after 12 weeks.
MEASUREMENTS: Outcomes were assessed after 12 and 24
weeks of intervention. Outcome measures included
neuropsychological testing (trail-making speed (NAI-ZVT-G),
digit memory span (NAI-ZN-G), and verbal learning
(NAI-WL)), clinical assessment (presence and severity of
geriatric symptoms (SCAG), depressive mood (GDS),
self-perceived health and memory status (report marks)),
and behavioral assessment (self-reported level of
instrumental daily life activities).
RESULTS: An intention-to-treat analysis showed no effect
on each of the outcome measures for participants who were
assigned to ginkgo (n = 79) compared with placebo (n = 44)
for the entire 24-week period. After 12 weeks of treatment,
the combined high dose and usual dose ginkgo groups (n =
166) performed slightly better with regard to self-reported
activities of daily life but slightly worse with regard to
self-perceived health status compared with the placebo
group (n = 48). No beneficial effects of a higher dose or a
prolonged duration of ginkgo treatment were found. We could
not detect any subgroup that benefited from ginkgo. Ginkgo
use was also not associated with the occurrence of
(serious) adverse events.
CONCLUSIONS: The results of our trial suggest that
ginkgo is not effective as a treatment for older people
with mild to moderate dementia or age-associated memory
impairment. Our results contrast sharply with those of
previous ginkgo trials.
Cholinesterase
inhibitors and Gingko extracts--are they comparable in the
treatment of dementia? Comparison of published
placebo-controlled efficacy studies of at least six months'
duration.
Wettstein A Stadtarztlicher Dienst, Zurich.
albert.wettstein@gud.stzh.ch
Phytomedicine 2000 Jan;6(6):393-401
The efficacy of four cholinesterase inhibitors (tacrine,
donepezil, rivastigmine, metrifonate) and Ginkgo special
extract EGb 761 in Alzheimer's disease were compared. The
differences in the effects of the active substance and
placebo on cognition were measured on the ADAS-Cog scale,
taking into account the different degrees of dementia in
the various studies and the dropout rate due to adverse
drug reactions. Efficacy, expressed as the delay in symptom
progression or the difference in response rate between
active substance and placebo, showed no major differences
between the four cholinesterase inhibitors and the Ginkgo
special extract. Only tacrine exhibited a high dropout rate
due to adverse drug reactions. In view of this, the subject
of new prescriptions should be critically reviewed.
Second-generation cholinesterase inhibitors (donepezil,
rivastigmine, metrifonate) and Ginkgo special extract EGb
761 should be considered equally effective in the treatment
of mild to moderate Alzheimer's dementia.
Efficacy of tablet
huperzine-A on memory, cognition, and behavior in
Alzheimer's disease.
Xu SS, Gao ZX, Weng Z, Du ZM, Xu WA, Yang JS, Zhang ML,
Tong ZH, Fang YS, Chai XS, et al. Zhejiang Supervision and
Detection Station of Drug Abuse, Zhejiang Medical
University, Hangzhou, China.
Zhongguo Yao Li Xue Bao 1995 Sep;16(5):391-5
AIM: To evaluate the efficacy and safety of tablet
huperzine-A (Hup) in patients with Alzheimer's disease.
METHODS: Using multicenter, prospective, double-blind,
parallel, placebo controlled and randomized method, 50
patients were administered orally 0.2 mg (4 tablets) Hup
and 53 patients were given po 4 tablets of placebo bid for
8 wk. All patients were evaluated with Wechsler memory
scale, Hasegawa dementia scale, mini-mental state
examination scale, activity of daily living scale,
treatment emergency symptom scale, and measured with BP,
HR, ECG, EEG, ALT, AKP, BUN, Cr, Hb, WBC, and urine
routine.
RESULTS: About 58% (29/50) of patients treated with Hup
showed improvements in their memory (P < 0.01),
cognitive (P < 0.01), and behavioral (P < 0.01
functions. The efficacy of Hup was better than placebo
(36%, 19/53) (P < 0.05). No severe side effect was
found.
CONCLUSION: Hup is a promising drug for symptomatic
treatment of Alzheimer's disease.
Estrogen therapy in
postmenopausal women: effects on cognitive function and
dementia.
Yaffe K, Sawaya G, Lieberburg I, Grady D. Department of
Psychiatry, University of California, San Francisco 94121,
USA. kyaffe@itsa.ucsf.edu
JAMA 1998 Mar 4;279(9):688-95
CONTEXT: Several studies have suggested that estrogen
replacement therapy in postmenopausal women improves
cognition, prevents development of dementia, and improves
the severity of dementia, while other studies have not
found a benefit of estrogen use. OBJECTIVE: To determine
whether postmenopausal estrogen therapy improves cognition,
prevents development of dementia, or improves dementia
severity. DATA SOURCES: We performed a literature search of
studies published from January 1966 through June 1997,
using MEDLINE, manually searched bibliographies of articles
identified, and consulted experts.
STUDY SELECTION: Studies that evaluated biological
mechanisms of estrogen's effect on the central nervous
system and studies that addressed the effect of estrogen on
cognitive function or on dementia.
DATA EXTRACTION: We reviewed studies for methods,
sources of bias, and outcomes and performed a meta-analysis
of the 10 studies of postmenopausal estrogen use and risk
of dementia using standard meta-analytic methods.
DATA SYNTHESIS: Biochemical and neurophysiologic studies
suggest several mechanisms by which estrogen may affect
cognition: promotion of cholinergic and serotonergic
activity in specific brain regions, maintenance of neural
circuitry, favorable lipoprotein alterations, and
prevention of cerebral ischemia. Five observational studies
and 8 trials have addressed the effect of estrogen on
cognitive function in nondemented postmenopausal women.
Cognition seems to improve in perimenopausal women,
possibly because menopausal symptoms improve, but there is
no clear benefit in asymptomatic women. Ten observational
studies have measured the effect of postmenopausal estrogen
use on risk of developing dementia. Meta-analysis of these
studies suggests a 29% decreased risk of developing
dementia among estrogen users, but the findings of the
studies are heterogeneous. Four trials of estrogen therapy
in women with Alzheimer disease have been conducted and
have had primarily positive results, but most have been
small, of short duration, non-randomized, and
uncontrolled.
CONCLUSIONS: There are plausible biological mechanisms
by which estrogen might lead to improved cognition, reduced
risk for dementia, or improvement in the severity of
dementia. Studies conducted in women, however, have
substantial methodologic problems and have produced
conflicting results. Large placebo-controlled trials are
required to address estrogen's role in prevention and
treatment of Alzheimer disease and other dementias. Given
the known risks of estrogen therapy, we do not recommend
estrogen for the prevention or treatment of Alzheimer
disease or other dementias until adequate trials have been
completed.
Protective effects of
idebenone and alpha-tocopherol on
beta-amyloid-(1-42)-induced learning and memory deficits in
rats: implication of oxidative stress in
beta-amyloid-induced neurotoxicity in vivo.
Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T,
Nabeshima T. Department of Neuropsychopharmacology and
Hospital Pharmacy, Nagoya University School of Medicine,
Japan.
Eur J Neurosci 1999 Jan;11(1):83-90
Amyloid beta-peptide (A beta), the major constituent of
the senile plaques in the brains of patients with
Alzheimer's disease, is cytotoxic to neurons and has a
central role in the pathogenesis of the disease. Previous
studies have suggested that oxidative stress is involved in
the mechanisms of A beta-induced neurotoxicity in vitro. In
the present study, we examined whether oxidative stress
contributes to learning and memory deficits caused by
continuous intracerebroventricular infusion of A
beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous
alternation behaviour in a Y-maze and spatial memory in a
water maze task were significantly impaired, as compared
with A beta-(40-1)-infused control rats. The retention of
passive avoidance learning was also significantly impaired
by treatment with A beta-(1-42). Potent antioxidants
idebenone and alpha-tocopherol prevented the behavioural
deficits in Y-maze and water maze, but not passive
avoidance, tasks in A beta-(1-42)-infused rats when they
were repeatedly administered by mouth once a day from 3
days before the start of A beta infusion to the end of
behavioural experiments. Lipid peroxide levels in the
hippocampus and cerebral cortex of A beta-(1-42)-infused
rats did not differ from those in control animals, and
neither idebenone nor alpha-tocopherol affected the lipid
peroxide levels. These results suggest that treatment with
antioxidants such as idebenone and alpha-tocopherol
prevents learning and memory deficits caused by A beta.
Orally active NGF
synthesis stimulators: potential therapeutic agents in
Alzheimer's disease.
Yamada K; Nitta A; Hasegawa T; Fuji K; Hiramatsu M;
Kameyama T; Furukawa Y; Hayashi K; Nabeshima T Department
of Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University School of Medicine, Japan.
Behav Brain Res (Netherlands) Feb 1997, 83 (1-2)
p117-22
The degeneration of cholinergic neurons may be
responsible for cognitive impairment in patients with
Alzheimer's disease (AD). Since nerve growth factor (NGF)
plays an important role in the survival and maintenance of
cholinergic neurons in the central nervous system, this
factor may have some beneficial effects on the cognitive
impairment observed in patients with AD. However, since NGF
does not cross the blood-brain barrier and is easily
metabolized when administered peripherally, it can only be
used when directly injected into the brain. In this review,
we show that repeated oral administration of the NGF
synthesis stimulators, idebenone and propentofylline,
partially restored the age-associated decrease of NGF in
the frontal and parietal cortices. Furthermore, this
treatment attenuated the impairment of performance in the
water maze, passive avoidance, and habituation tasks in
rats with bilateral forebrain lesions, and in rats which
had received continuous infusion of anti-NGF antibody into
the septum. The behavioral improvement induced by idebenone
and propentofylline was accompanied by recovery of both the
reduced activity of choline acetyltransferase and the
changes in [3H]QNB binding. These results suggest that the
use of NGF synthesis stimulators may provide a novel
therapeutic approach to cholinergic dysfunction. (32 Refs.)
(NOTE: Idebenone and propentophylline are drugs that can be
ordered from offshore pharmacies.)
Free radicals and lipid
peroxidation do not mediate beta-amyloid-induced neuronal
cell death.
Yao ZX, Drieu K, Szweda LI, Papadopoulos V. Division of
Hormone Research, Departments of Cell Biology and
Pharmacology, Georgetown University Medical Center, 3900
Reservoir Road, NW, Washington, DC 20007, USA.
Brain Res 1999 Nov 20;847(2):203-10
"beta Amyloid (Abeta)-induced free radical-mediated
neurotoxicity" is a leading hypothesis as a cause of
Alzheimer's disease (AD). Abeta increased free radical
production and lipid peroxidation in PC12 nerve cells,
leading to increased 4-hydroxy-2-nonenal (HNE) production
and modification of specific mitochondrial target proteins,
apoptosis and cell death. Pretreatment of the cells with
isolated ginkgolides, the anti-oxidant component of Ginkgo
biloba leaves, or vitamin E, prevented the Abeta-induced
increase of reactive oxygen species (ROS). Ginkgolides, but
not vitamin E, inhibited the Abeta-induced HNE modification
of mitochondrial proteins. However, treatment with these
anti-oxidants did not rescue the cells from Abeta-induced
apoptosis and cell death. These results indicate that free
radicals and lipid peroxidation may not mediate
Abeta-induced neurotoxicity.
The Ginkgo biloba
extract EGb 761 rescues the PC12 neuronal cells from
beta-amyloid-induced cell death by inhibiting the formation
of beta-amyloid-derived diffusible neurotoxic
ligands.
Yao Z, Drieu K, Papadopoulos V. Division of Hormone
Research, Departments of Cell Biology, Pharmacology, and
Neuroscience, Georgetown University Medical Center, 3900
Reservoir Road, NW, Washington, DC 20007, USA.
Brain Res 2001 Jan 19;889(1-2):181-90
beta Amyloid (Abeta) treatment induced free radical
production and increased glucose uptake, apoptosis and cell
death in PC12 nerve cells. Addition of the standardized
extract of Ginkgo biloba leaves, EGb 761 together with the
Abeta protein prevented, in a dose-dependent manner, the
Abeta-induced free radical production, increased glucose
uptake, apoptosis and cell death. However, pretreatment of
the cells with EGb 761 did not rescue the cells from the
Abeta-induced toxicity although it prevented the
Abeta-induced reactive oxygen species generation. Moreover,
the terpene and flavonoid-free EGb 761 extract, HE 208,
although inhibited the Abeta-induced increased glucose
uptake, it failed to protect the cells from apoptosis and
cytotoxicity induced by Abeta. In conclusion, these results
indicate that the terpenoid and flavonoid constituents of
EGb 761, acting probably in combination with components
present in HE 208, are responsible for rescuing the
neuronal cells from Abeta-induced apoptosis and cell death;
their mechanism of action being distinct of their
antioxidant properties. Because pre- and post-treatment
with EGb 761 did not protect the cells from Abeta-induced
neurotoxicity, we examined whether EGb 761 interacts
directly with Abeta. Indeed, in vitro reconstitution
studies demonstrated that EGb 761 inhibits, in a
dose-dependent manner, the formation of
beta-amyloid-derived diffusible neurotoxic soluble ligands
(ADDLs), suggested to be involved in the pathogenesis of
Alzheimer's disease.
Alzheimer's amyloid
beta-peptide associated free radicals increase rat
embryonic neuronal polyamine uptake and ornithine
decarboxylase activity: protective effect of vitamin
E.
Yatin SM, Yatin M, Aulick T, Ain KB, Butterfield DA.
Department of Chemistry, Sanders-Brown Center of Aging,
University of Kentucky, Lexington 40506-0055, USA.
Neurosci Lett 1999 Mar 19;263(1):17-20
Recent evidence indicates that alterations in brain
polyamine metabolism may be critical for nerve cell
survival after a free radical initiated neurodegenerative
process. It has been shown previously that A beta(1-42) and
A beta(25-35) are toxic to neurons through a free radical
dependent oxidative mechanism. Treatment of rat embryonic
hippocampal neuronal cultures with A beta-peptides
increased ornithine decarboxylase (ODC) activity and
spermidine uptake, suggesting that oxidative stress
upregulates the polyamine mechanism for the repair of free
radical damage. Pretreatment of the cells with vitamin E
prior to A beta exposure decreased ODC activity and
spermidine uptake to control level. This study is the first
to demonstrate that A beta treated cells show an increased
polyamine metabolism in response to free radical mediated
oxidative stress and that the free radical scavenger
vitamin E prevents these attenuations. These results are
discussed with reference to Alzheimer's disease.
Essential fatty acids
preparation (SR-3) improves Alzheimer's patients quality of
life.
Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI.
Department of Psychology Bar-Ilan University, Ramat Gan,
Israel.
Int J Neurosci 1996 Nov;87(3-4):141-9
In a number of previous reports we showed the salutary
effects on rats of SR-3, a compound comprising a 1:4 ratio
of n-3 and n-6 fatty acids. Improvements were noted in
learning tasks, thermoregulation, recovery from
neurotoxins, and seizure protection. Because we were
impressed that these effects are related to changes in
membrane fluidity and neuronal functioning and because
Alzheimer's Disease is also associated with lipid defects,
we undertook a short term (4 week) double blind study with
100 Alzheimer patients (60 received SR-3 and 40 in a
placebo control). The results indicated improvements in
mood, cooperation, appetite, sleep, ability to navigate in
the home, and short term memory. Overall improvement was
reported for 49 patients, and in no case did a guardian
report adverse effects to the compound. While not uniform
or permanent, and while no mode of action for SR-3 can be
precisely identified at this time, the promising results in
quality of life for the patient and caregiver warrant
further clinical trials and continued basic research into
the neuropsychological substrate of the disease and its
response to SR-3.
Essential fatty acids
and the brain: possible health implications.
Youdim KA, Martin A, Joseph JA. Laboratory of
Neuroscience, United States Department of Agriculture, Jean
Mayer Human Nutrition Research Center on Aging at Tufts
University, Boston, MA, USA. kyoudim@hnrc.tufts.edu
Int J Dev Neurosci 2000 Jul-Aug;18(4-5):383-99
Linoleic and alpha-linolenic acid are essential for
normal cellular function, and act as precursors for the
synthesis of longer chained polyunsaturated fatty acids
(PUFAs) such as arachidonic (AA), eicosapentaenoic (EPA)
and docosahexaenoic acids (DHA), which have been shown to
partake in numerous cellular functions affecting membrane
fluidity, membrane enzyme activities and eicosanoid
synthesis. The brain is particularly rich in PUFAs such as
DHA, and changes in tissue membrane composition of these
PUFAs reflect that of the dietary source. The decline in
structural and functional integrity of this tissue appears
to correlate with loss in membrane DHA concentrations.
Arachidonic acid, also predominant in this tissue, is a
major precursor for the synthesis of eicosanoids, that
serve as intracellular or extracellular signals. With aging
comes a likely increase in reactive oxygen species and
hence a concomitant decline in membrane PUFA
concentrations, and with it, cognitive impairment.
Neurodegenerative disorders such as Parkinson's and
Alzheimer's disease also appear to exhibit membrane loss of
PUFAs. Thus it may be that an optimal diet with a balance
of n-6 and n-3 fatty acids may help to delay their onset or
reduce the insult to brain functions which these diseases
elicit.
Reactive oxygen
species-induced apoptosis in PC12 cells and protective
effect of bilobalide.
Zhou LJ, Zhu XZ Department of Pharmacology, Shanghai
Institute of Materia Medica, Chinese Academy of
Sciences.
J Pharmacol Exp Ther 2000 Jun;293(3):982-8
Although clinical studies have demonstrated that EGb
761, a standard extract of Ginkgo biloba, was effective in
mild-to-moderate dementia of the Alzheimer's disease
patients, the mechanism underlying its neuroprotective
effect remains unclear. In this study, effects of
bilobalide, the main constituent of the nonflavone fraction
of EGb 761, on reactive oxygen species (ROS)-induced
apoptosis in PC12 cells was studied. Exposure of cells to
xanthine (100 microM)/xanthine oxidase (150 mU/ml) (ROS
producer) resulted in a characteristic DNA fragmentation
and an increase in the apoptosis rate. When p53, c-Myc,
Bcl-2, Bcl-x(L), and Bax were measured by flow cytometry
and the activities of caspase-1- and caspase-3-like
protease determined with Ac-YVAD-AMC or Ac-DEVD-AMC as
substrates, the profile of ROS-induced changes in these
apoptosis regulatory and effector proteins suggests that
elevation of c-Myc, p53, and Bax and activation of
caspase-3 play an important role in the apoptosis. When
cells were treated with ROS and bilobalide (25-100 microM)
simultaneously, a dose-dependent reduction in the apoptotic
rate was found. The percentage of cells with positive
staining for c-Myc and p53 decreased from 27.8 and 50.1% to
16.7 and 23.2%, respectively, when bilobalide (25 microM)
was present. Bilobalide also reduced ROS-induced elevation
of Bax and activation of caspase-3 effectively. Our results
provide the first direct evidence that bilobalide can
protect neurons against oxidative stress. Bilobalide may
block the apoptosis in the early stage and then attenuate
the elevation of c-Myc, p53, and Bax and activation of
caspase-3 in cells.
Idebenone -
monograph.
Anon
Altern Med Rev 2001 Feb;6(1):83-6
No abstract available Full page editorial found here
http://www.thorne.com/altmedrev/.fulltext/6/1/83.html
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