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Favourable effects of nilvadipine on cognitive function and regional cerebral blood flow on SPECT in hypertensive patients with mild cognitive impairment
Abstract
We compared the effects of nilvadipine and amlodipine on the cognitive function and regional cerebral blood flow (rCBF) in patients with mild cognitive impairment (MCI) and hypertension.
Twelve patients with MCI and hypertension were randomly assigned to receive nilvadipine or amlodipine for 12-16 weeks. Before and after treatment all patients underwent neuropsychological evaluation and single photon emission computed tomography (SPECT) studies with N-isopropyl-p-[123I]iodoamphetamine.
Both nilvadipine (n=6) and amlodipine (n=6) groups had similar significant reduction in systolic and diastolic blood pressure after treatment. The Logical Memory subscore of the Wechsler Memory Scale-Revised increased significantly in the nilvadipine group, but not in the amlodipine group after treatment. Although SPECT demonstrated no significant differences in rCBF deficits at baseline between the two groups, the nilvadipine group showed an improvement of rCBF in the left frontal lobe, while the amlodipine group showed a decrease of rCBF in the left temporal lobe.
Our results suggest that nilvadipine, a highly lipophilic agent that easily penetrates the central nervous system, may have additional benefits and be potentially useful for the treatment of patients with MCI and hypertension.
... The study characteristics of the 32 included studies are presented in Table 1. Fourteen studies were randomized controlled trial's, [26][27][28][29][30][31][32][33][34][35][36][37][38][39] one was a nonrandomized trial (comparing hydrochlorothiazide with no medication without randomizing the groups) 40 and seventeen were prestudies and poststudies, 41-57 6 of which used a cross-over design. 28,[37][38][39][40]46 Twenty-three studies investigated chronic effects of AHT, 26 ...
... Thirteen studies investigated regional CBF. 26,28,29,31,32,34,36,42,47,49,50,52,54 Only 5 studies showed significant changes (mostly increases) in CBF in specific brain regions. 26,29,31,52,54 However, these regions were not consistent across the 5 studies. ...
... 26,28,29,31,32,34,36,42,47,49,50,52,54 Only 5 studies showed significant changes (mostly increases) in CBF in specific brain regions. 26,29,31,52,54 However, these regions were not consistent across the 5 studies. One study showed a significant increase in CBF in the left hippocampal region after treatment with nilvadipine. ...
Background
In older age, the benefits of antihypertensive treatment (AHT) become less evident, with greater associated risk. Of particular concern is compromising cerebral blood flow (CBF), especially in those with cognitive impairment.
Methods
We created a synthesis of the published evidence by searching multiple electronic databases from 1970 to May 2021. Included studies had participants with mean age ≥50 years, hypertension and cognitive impairment, and assessed CBF before and after initiating AHT. Two authors independently determined eligibility and extracted data. Study quality was assessed using The Risk of Bias in Nonrandomized Studies of Interventions tool. We summarized study characteristics (qualitative synthesis) and performed random-effects meta-analyses (quantitative synthesis).
Results
Thirty-two studies (total n=1306) were included, of which 23 were eligible for meta-analysis. In line with the qualitative synthesis, the meta-analysis indicated no effect of AHT initiation on CBF (standardized mean difference, 0.08 [95% CI, −0.07 to 0.22]; P =0.31, I ² =42%). This was consistent across subgroups of acute versus chronic AHT, drug class, study design, and CBF measurement. Subgroups by age demonstrated an increase in CBF after AHT in those aged >70 years (standardized mean difference, 4.15 [95% CI, 0.16–8.15]; P =0.04, I 2 =42%), but not in those aged 50 to 65 and 65 to 70 years (standardized mean difference, 0.18 [95% CI,−2.02 to 2.38]; P =0.87, I 2 =49%; standardized mean difference, 1.22 [95% CI, −0.45 to 2.88]; P =0.15, I 2 =68%). Overall, risk of bias was moderate-to-high and quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) was very low, reflecting the observational nature of the data.
Conclusions
Accepting the observed limitations, current evidence does not suggest a harmful effect of AHT on CBF. Concerns over CBF should not preclude treatment of hypertension.
... The full text of 31 RCTs was examined and a total of 16 studies were excluded. Fifteen RCTs were included in the final systematic review [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Out of the 15 studies, 8 were double-blind, 1 was single-blind, and 6 were open-label. ...
... The RCTs in the Table 1 included several different drug groups: ARBs, ACE-Is, BBs, DIUs, and CCBs. ARBs seem to improve cerebrovascular hemodynamics and preserve executive function, whereas ACE-Is do not possess such benefit [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. An ARB-based regime in older adults with hypertension and mild executive dysfunction may also be associated with retained executive function and blood flow velocity. ...
... One study showed that an ACE-I compared to a BB improved choice reaction time [21]. In a study with small effect size (n = 6 in both groups), two CCBs were compared and the results showed that nilvadipine, but not amlodipine improved logical memory [22]. ...
Background:
Chronic hypertension has been associated with an increased risk of cognitive decline. Although a link between hypertension and cognitive decline has been established, there is less evidence supported by systematic reviews. The main aim was to compare different antihypertensive drug groups in relation to their effect on cognition in older patients without established dementia using a systematic review.
Method:
A systematic search in Medline and Embase through to January 2017 was used to identify randomized controlled clinical trials (RCTs) studying the impact of different antihypertensives on cognition in older patients without dementia. Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE-Is), beta-blockers (BBs), diuretics, and calcium channel blockers (CCBs) were included in this review.
Results:
The systematic search identified 358 studies. The full text of 31 RCTs was reviewed and a total of 15 RCTs were included in the review. Most studies reported an improvement in episodic memory in patients treated with ARBs versus placebo or other types of antihypertensive drugs. No study showed an improvement in cognition in patients who received diuretics, BBs, or CCBs. Heterogeneity was high in most trials (predominantly in the blinding of participants and investigators).
Conclusion:
This review suggests that ARBs can improve cognitive functions in the elderly, especially episodic memory. ACE-Is, diuretics, BBs and CCBs did not seem to improve cognitive function in the elderly but were similarly effective in blood pressure lowering as ARBs.
Keywords:
Geriatric psychiatry and aging; Neurology; Psychopharmacology; Neuroscience; Cognition
... Treatment with nilvadipine, but not amlodipine, in hypertensive patients with mild cognitive impairment was shown to prevent further cognitive decline for up to 20 months (Hanyu et al., 2007a) and was associated with an improvement in CBF measured using SPECT (Hanyu et al., 2007a). However treatment groups were rather small (less than 10 subjects) and subjects who progressed to AD were omitted from the longitudinal analyses. ...
... Treatment with nilvadipine, but not amlodipine, in hypertensive patients with mild cognitive impairment was shown to prevent further cognitive decline for up to 20 months (Hanyu et al., 2007a) and was associated with an improvement in CBF measured using SPECT (Hanyu et al., 2007a). However treatment groups were rather small (less than 10 subjects) and subjects who progressed to AD were omitted from the longitudinal analyses. ...
... Our findings, similar to Hanyu and colleagues (Hanyu et al., 2007a;Hanyu et al., 2007b), indicate that nilvadipine has modifying effects on cognition. In our AD group, treatment with nilvadipine stabilized cognition over the short treatment period. ...
Background
The physical form of the hospital environment shapes the care setting and influences the relationship of the hospital to the community. Due to ongoing demographic change, evolving public health needs, and advancing medical practice, typical hospitals are frequently redeveloped, retrofitted, or expanded. It is argued that multi-disciplinary and multi-stakeholder approaches are required to ensure that hospital design matches these increasingly complex needs. To facilitate such a conversation across different disciplines, experts, and community stakeholders, it is helpful to establish a hospital typology and associated terminology as part of any collaborative process. AimsExamine the literature around hospital design, and review the layout and overall form of a range of typical Irish acute public hospitals, to outline an associated building typology, and to establish the terminology associated with the planning and design of these hospitals in Ireland. Methods
Searches in ‘Academic Search Complete’, ‘Compendex’, ‘Google’, ‘Google Scholar’, ‘JSTOR’, ‘PADDI’, ‘Science Direct’, ‘Scopus’, ‘Web of Science’, and Trinity College Dublin Library. The search terms included: ‘hospital design history’; ‘hospital typology’; ‘hospital design terminology’; and ‘hospital design Ireland’. ResultsTypical hospitals are composed of different layouts due to development over time; however, various discrete building typologies can still be determined within many hospitals. This paper presents a typology illustrating distinct layout, circulation, and physical form characteristics, along with a hospital planning and design terminology of key terms and definitions. Conclusion
This typology and terminology define the main components of Irish hospital building design to create a shared understanding around design, and support stakeholder engagement, as part of any collaborative design process.
... Treatment with nilvadipine, but not amlodipine, in hypertensive patients with mild cognitive impairment was shown to prevent further cognitive decline for up to 20 months (Hanyu et al., 2007a) and was associated with an improvement in CBF measured using SPECT (Hanyu et al., 2007a). However treatment groups were rather small (less than 10 subjects) and subjects who progressed to AD were omitted from the longitudinal analyses. ...
... Treatment with nilvadipine, but not amlodipine, in hypertensive patients with mild cognitive impairment was shown to prevent further cognitive decline for up to 20 months (Hanyu et al., 2007a) and was associated with an improvement in CBF measured using SPECT (Hanyu et al., 2007a). However treatment groups were rather small (less than 10 subjects) and subjects who progressed to AD were omitted from the longitudinal analyses. ...
... Our findings, similar to Hanyu and colleagues (Hanyu et al., 2007a;Hanyu et al., 2007b), indicate that nilvadipine has modifying effects on cognition. In our AD group, treatment with nilvadipine stabilized cognition over the short treatment period. ...
... In patients with hypertension and mild cognitive impairment, nilvadipine, but not amlodipine, increased regional CBF. 37 Theoretically, nilvadipine could also reduce amyloid-β deposition in the vascular wall by facilitating clearance 38 ; however, it is unlikely that this would show such strong effects in 6 months. ...
... Our findings cannot yet be translated to earlier stages of the disease, although a previous study in a small group of mild cognitive impairment because patients with AD showed similar results. 37 Patients with a diastolic pressure <60 mm Hg and a pulse pressure >60 mm Hg, which could indicate increased vascular stiffness, may be at increased risk of lobar ischemia after BP lowering. 32 None of our participants met these criteria, and, therefore, our findings cannot be extrapolated to such patients. ...
Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=−11.5 [95% CI, −19.7 to −3.2] mm Hg; P <0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, −6.4 to 17.2] mL/100 g per minute; P =0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3–44.5] mL/100 g per minute; P =0.02; right: Δ=20.1 [95% CI, −0.6 to 40.8] mL/100 g per minute; P =0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, −16.5 to 27.0] mL/100 g per minute; P =0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.
... Данные литературы о влиянии амлодипина на когнитивные функции противоречивы [23][24][25][26]. В некоторых исследованиях выявлено их улучшение на фоне лечения амлодипином. ...
... [24] выявили уменьшение когнитивного дефицита на фоне лечения амлодипином у пациентов среднего возраста с АГ, хотя и с большей средней длительностью заболевания (7,7±0,9 лет) и более высокими исходными уровнями АД (среднее АД 170,3±16,2/96,6±7,2 мм рт.ст.), а также с наличием сопутствующих заболеваний (стенокардия, постинфарктный кардиосклероз), которые влияют на состояние когнитивных функций. Однако в других исследованиях не было выявлено улучшения когнитивных функций на фоне лечения амлодипином [25,26], возможно, из-за малого объема выборки. ...
Different antihypertensive drugs differently affect cognitive function, and data on the effect of single-pill combination (SPC) of antihypertensive drugs on cognitive function are presented only in single studies.
Aim . To investigate the impact of amlodipine/valsartan SPC (A/V SPC) on blood pressure (BP) level and cognitive functions in the middle-aged antihypertensive treatment-naive patients with stage II grade 1-2 essential arterial hypertension.
Methods . A group of patients with stage II grade 1-2 essential arterial hypertension who had not previously received regular antihypertensive treatment (n=38, age 49.7±7.0 years) was retrospectively formed. All the patients were treated with A/V SPC and all of them achieved target office BP (less than 140/90 mm Hg). And after 12-week follow-up (since the time of reaching the target BP) the antihypertensive treatment efficacy assessment using ambulatory BP monitoring (ABPM) were performed in all included hypertensive patients. Age-matched healthy people with normal BP (n=20, mean age 45.4±5.1years) represented a control group. In all participants cognitive functions were evaluated by 5 different tests at baseline and at the end of follow-up: Montreal Cognitive Assessment (MoCA); Trail Making test (part A and part B), Stroop Color and Word Test; verbal fluency test; 10-item word list learning task. Baseline Hamilton depression and anxiety rating scale data were also available in all individuals.
Results . According to the ABPM data 24-hour, day-time and night-time systolic, diastolic and pulse BP significantly decreased after the treatment with A/V SPC (p<0.001 for systolic and diastolic BP and p<0.01 for pulse BP). After the treatment with A/V SPC significantly improved results of cognitive tests in hypertensive patients: decreased time in Trail Making Test part B (from 114.7±37.0 to 96.3±26.5 s; р=0.001); time difference between part B and part A of Trail Making Test (from 75.2±32.8 to 57.7±20.1 s; р=0.002); time in Stroop test part 3 (from 117.0±28.1 to 108.0±28.4 s; р=0.013); and interference score (from 50.9±19.2 to 43.1±22.0 s; р=0.011); increased MoCA score (from 28.4±1.3 to 29.4±1.2; р=0.001); as well as increased the 10-item word list learning task – immediate recall (from 5.7±1.3 to 6.5±1.2 words; р=0.001); 10-item word list learning task – delayed recall (from 6.3±2.1 to 6.9±1.7 words; р=0.006); literal fluency (from 11.7±3.4 to 13.2±3.2 words; р=0.020) and categorical fluency (from 7.3±2.5 to 9.5±2.9 words; p<0.001). In control group at the end of follow-up compared to baseline significantly increased the 10-item word list learning task – immediate recall (from 5.8±0.9 to 6.6±1.1 words; р<0.05) and delayed recall (from 5.9±1.8 to 8.2±1.4 words; р<0.001).
Conclusion . In retrospective analysis improvement of cognitive function was found in middle-aged patients with hypertension, taking A/V SPC for 12 weeks after reaching the target BP.
... At present there is virtually no information regarding behavioural or cognitive effects of current LTCC antagonists. Low-quality evidence has demonstrated potential beneficial effects on cerebrovascular cognitive impairment [10,11]; an electronic health records study has suggested differential admission rates for persons taking LTCC antagonists for depression compared to people taking other antihypertensives [12], and some rodent studies have indicated improved performance on cognitive tasks after administration of LTCC antagonists [13][14][15][16]. ...
... Participants are presented with an array of 11 'L's and one 'T' and asked to tap on the 'T' as quickly as possible. There Happiness is rated before and after each game on a 21-point scale, from unhappy (− 10), through neutral (0), to happy (10). Participants are emailed each day with a reminder to complete the tasks. ...
Background
The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour.
Methods
The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737.
Discussion
The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected.
Trial registration
ISRCTN, ISRCTN33631053. Retrospectively registered on 8 June 2018 (applied 17 May 2018).
Electronic supplementary material
The online version of this article (10.1186/s13063-019-3175-0) contains supplementary material, which is available to authorized users.
... Calcium channel blockers are drugs used to treat hypertension and angina. The dihydropyridine calcium channel blockers, such as nilvadipine (20), can reduce the production, oligomerization and accumulation of amyloid-β in vitro, improve cell survival and reduce neurotoxicity, while having good blood-brain barrier penetration and increasing brain blood flow through its vasodilatory properties [50][51][52]. ...
... Taking this into account, anti-HIV drugs can be helpful for ALS. Triumeq ® is a combination of dolutegravir (50), an integrase inhibitor, abacavir (51) and lamivudine (52), antiretrovirals, and has shown safety and tolerability in ALS patients [13]. ...
Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
... Nilvadipine is a clinically used antihypertensive that we have shown to be well tolerated and to stabilize cognition in AD patients compared with untreated patients (21,22). Interestingly, long term use of nilvadipine in subjects with mild cognitive impairment has also been shown to prevent cognitive decline and to reduce the incidence of AD conversion (23) suggesting that nilvadipine may have disease-modifying benefits. Nilvadipine consists of a mixture of two enantiomers, (ϩ)nilvadipine and (Ϫ)-nilvadipine, in equal proportion. ...
... Chronic treatment with nilvadipine has been shown to prevent the conversion of mild cognitive impairment to AD (23) suggesting that nilvadipine may have disease-modifying properties. In addition, a short treatment duration with nilvadipine in AD patients has been shown to reduce cognitive decline (21,22). ...
... For example, a pilot trial reported that hypertension management with nilvadipine versus amlodipine might improve cerebral blood flow in patients with MCI despite similar effects on blood pressure [34]. Currently, a trial is underway at the Sunnybrook Research Institute in Canada to compare hypertension management with telmisartan versus perindopril in patients with comorbid Alzheimer's, looking at global brain atrophy over one year (Table 1). ...
... DHP CCBs varied in their capacity to increase amyloid clearance from the brain [64]. Effects on the brain may vary depending on their selectivity for different calcium channels [65] In a small trial in hypertensive patients with MCI, nilvadipine versus amlodipine slowed cognitive decline and improved cerebral blood flow despite similar effects on blood pressure [34]. Nitrendipine and nimodipine, have clinical data to suggest utility for the prevention or treatment of dementia, respectively, while nifedipine was associated with an increased risk of cognitive decline (reviewed in [64] GLP-1 agonists have been shown to protect against hippocampal synapse loss, lower beta-amyloid pathology and related damage, reduce neuroinflammation, and promote neurogenesis. ...
Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia.
... Nivaldipine [63,69] and isradipine [70] are the most promising CCBs for the treatment of AD and other forms of dementia. Specifically, nivaldipine retarded the progression of cognitive decline in patients with mild cognitive impairment [71,72]. Besides, it stabilized cognition and improved executive function in AD patients. ...
... It also normalizes CBF in the transgenic AD mouse model Tg APPsw [223] (Fig. 4D). The beneficial effect of nivaldipine on regional blood flow has been demonstrated also in human AD patients [72]. Therefore, CCBs may be helpful in AD not only because of their direct neuroprotective effects but also because they prevent the effect of AP on CBF. ...
It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca(2+) in neurons. Also, some of them as L-type channels are essential for Ca(2+)-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the "harmless" VGCCs may become "toxic" for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca(2+) when: a) their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca(2+)-dependent action potentials carry high Ca(2+) loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca(2+). This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca(2+)-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia.
... Consequently, vasoconstriction of the cerebral blood vessels, promoted by high intracellular calcium, reduces blood flow to the surrounding brain tissue. Dihydropyridines have the ability to prevent this by encouraging vasodilation (Hanyu et al., 2007). In addition, consistently high intracellular calcium levels, induced by chronic hypoperfusion, are thought to be favourable to the cleavage of the β-amyloid protein precursor by β-secretase, to produce the β-amyloid peptide (Kawahara & Kuroda, 2001). ...
... In addition, nilvadipine is highly selective for cerebral blood vessels [36], and improves cerebral circulation more than other CCBs [34]. Nilvadipine reaches the central nervous system in higher concentrations than other CCBs, and may increase regional cerebral blood flow [37,38]. In animal studies, CCBs increased blood flow in the choroid, retina, and optic disc [30][31][32]. ...
We investigated whether nilvadipine has a neuroprotective effect on retinal ganglion cells (RGCs) in a mouse model of ocular hypertension (OH) that expresses cyan fluorescein protein (CFP) in RGCs. OH was induced in the right eyes of Thy1-CFP transgenic mice using a laser. Nilvadipine or vehicle treatment began simultaneously with OH modeling and was administered intraperitoneally once daily for 8 weeks. Intraocular pressure (IOP) in both the laser- and non-treated eyes was measured weekly with the microneedle method, and calculations were performed to estimate the pressure insult in each eye. Using a retinal whole mount, the number of RGCs was counted at week 9. Laser-treated eyes showed a significant increase in IOP (p
... CCBs display excellent BBB permeability, maintain blood pressure, and suppress Aβinduced Ca 2+ release. 119,120 In this class of drugs, nimodipine was shown to attenuate Aβ-induced neurotoxicity via reducing the number of open Ca 2+ channels in cell membranes and restoring the controlled influx of Ca 2+ into the cells. 121 As a result, the downregulation of Ca 2+ levels due to action of nimodipine could enhance the α-secretase cleavage of APP, thus inhibiting amyloidogenesis. ...
The heterogeneity and complex nature of Alzheimer's disease (AD) is attributed to several genetic risk factors and molecular culprits. The slow pace and increasing failure rate of conventional drug discovery has led to the exploration of complementary strategies based on repurposing approved drugs to treat AD. Drug repurposing (DR) is a cost-effective, low-risk, and efficient approach for identifying novel therapeutic candidates for AD treatment. Similarly, hybrid drug design through the integration of distinct pharmacophores from known or failed drugs and natural products is an interesting strategy to target the multifactorial nature of AD. In this Perspective, we discuss the potential of DR and highlight promising drug candidates that can be advanced for clinical trials, backed by a detailed discussion on their plausible mechanisms of action. Our article fosters research on the hidden potential of DR and hybrid drug design with the goal of unravelling new drugs and targets to tackle AD.
... [75,76] Antihypertensives are especially linked to improved or preserved executive function, [75] processing speed, [76] and memory. [77,78] Treatment of hypertension is also thought to lower the incidence of AD, [79][80][81] and a postmortem study found that brains of individuals using hypertensive medications had less AD-related neuropathology than normotensive subjects, [82] while the Honolulu Asia Aging Study found that use of antihypertensives lowered risk for hippocampal atrophy. [83] Mouse models have demonstrated that antihypertensives can facilitate amyloid clearance across the blood-brain barrier. ...
... Most of the drugs in this class have good blood-brain barrier penetration and induces cerebral vasodilatation, increased cerebral blood flow in animals and humans [153]. In vitro studies have revealed that certain CCBs reduce Aβ production, oligomerization, and accumulation, rescue Aβ-induced neurotoxicity, and improve cell survival in the presence of Aβ [154][155][156]. ...
Drug repurposing is a strategy consisting of finding new indications for already known marketed drugs used in various clinical settings or highly characterized compounds despite they can be failed drugs. Recently, it emerges as an alternative approach for the rapid identification and development of new pharmaceuticals for various rare and complex diseases for which lack the effective drug treatments. The success rate of drugs repurposing approach accounts for approximately 30% of new FDA approved drugs and vaccines in recent years. This review focuses on the status of drugs repurposing approach for various diseases including skin diseases, infective, inflammatory, cancer, and neurodegenerative diseases. Efforts have been made to provide structural features and mode of actions of drugs.
... Nilvadipine has been shown to significantly improve memory and regional cerebral blood flow (rCBF) deficits in the left frontal lobe in hypertensive patients with MCI, while amlodipine did not. 31 In fact, regional cerebral blood flow in the temporal lobe of the amlodipine group deteriorated. The rCBF and cognitive effects were independent of the reduction in systolic and diastolic blood pressure after treatment. ...
Introduction
In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers.
Methods and analysis
All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78.
Ethics and dissemination
All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal.
Trial registration number
EUDRACT 2012-002764-27; Pre-results.
... Nilvadipine is a clinically used antihypertensive that we have shown to be well tolerated and to stabilize cognition in AD patients compared with untreated patients (21,22). Interestingly, long term use of nilvadipine in subjects with mild cognitive impairment has also been shown to prevent cognitive decline and to reduce the incidence of AD conversion (23) suggesting that nilvadipine may have disease-modifying benefits. Nilvadipine consists of a mixture of two enantiomers, (ϩ)nilvadipine and (Ϫ)-nilvadipine, in equal proportion. ...
We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixture of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-nilvadipine is the active enantiomer responsible for the inhibition of LCC whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aβ production and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (Tg Tau P301S) with (-)-nilvadipine reduces tau hyperphosphorylation at several AD pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compound inhibits the spleen tyrosine kinase (syk). We further validated syk as a target regulating Aβ by showing that pharmacological inhibition of syk or downregulation of syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and Tg Tau P301S mice with a selective syk inhibitor respectively decreased brain Aβ accumulation and tau hyperphosphorylation at multiple AD relevant epitopes. We show that syk inhibition induces an increased phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase-3β, a primary tau kinase involved in tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of tau phosphorylation at GSK3β dependent epitopes following syk inhibition. Altogether our data highlight syk as a promising target for preventing both Aβ accumulation and tau hyperphosphorylation in AD.
... Calcium Channel Blockers are a commonly used antihypertensive which elicit a vasodilatory effect on vascular tissue, and this effect has been recorded in the brain [57][58][59]. There is considerable clinical data to support the use of CCBs in AD, which has provided the rationale for further in vitro and in vitro studies to elucidate the mechanism. ...
Alzheimer's Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.
... This, in turn, may result in regional variations in drug exposure. Regional cerebral blood flow may be altered during disease states and by a variety of drugs, including anesthetic agents (Cole et al.,2007;Långsjö et al., 2005), anticonvulsants (Joo et al., 2006;Spanaki et al., 1999;Venneri, 2007), antidepressnts (Heideman et al., 1986) and antihypertensive drugs (Hanyu et al., 2007;Sare et al., 2008). Thus, a drug that affects regional cerebral blood flow may alter the regional distribution of itself, another drug, or related metabolites, that exhibit "flow limited" kinetics, such as desmethyl-loperamide (Liow et al., 2009). ...
There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug–drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs.
... A trend toward effectiveness was found for all substance groups. In the literature, the use of calcium antagonists, particularly nilvadipine because of its high lipophilic properties, and angiotensin receptor blockers were shown to have an advantage over other antihypertensive substance classes with regard to AD prevention (47)(48)(49). Whether particular antihypertensive agents bear a specific neuroprotective effect needs to be further validated. ...
BACKGROUND
Mid-life hypertension is associated with cognitive decline and dementia in later life. Reducing high blood pressure (BP) with antihypertensive agents is a well-researched strategy to prevent dementia and mild cognitive impairment (MCI). However, there is still limited direct evidence to support the approach, and particularly for the treatment of the very old and those with existing MCI.
METHODS
This review presents an overview of the current evidence for the relationship between MCI and hypertension, and of the potential pathophysiological mechanisms related to cognitive decline and incidence dementia in relation to aging.
RESULTS
Although observational data are near consistent in showing an association between mid-life hypertension and MCI and/or dementia, the evidence in relation to hypertension in younger adults and the very old (age >80 years) is much more limited. Most of the commonly available antihypertensive agents appear to provide beneficial effects in reducing the risk dementia, but there is limited evidence to support such treatment in those with existing MCI.
CONCLUSIONS
Further studies are needed to determine the optimal levels of BP control across different age groups, especially in adults with MCI, and which class(es) of antihypertensive agents and duration of treatment best preserve cognitive function in those at risk of, or with established, MCI.
Background
Alzheimer’s disease (AD) is one of the most severe neurodegenerative diseases leading to dementia in the elderly. Cerebral atrophy and hypoperfusion are two important pathophysiological characteristics. However, it is still unknown about the area-specific causal pathways between regional gray matter atrophy, cerebral hypoperfusion, and cognitive impairment in AD patients.
Method
Forty-two qualified AD patients and 49 healthy controls (HC) were recruited in this study. First, we explored voxel-wise inter-group differences in gray matter volume (GMV) and arterial spin labeling (ASL) -derived cerebral blood flow (CBF). Then we explored the voxel-wise associations between GMV and Mini-Mental State Examination (MMSE) score, GMV and CBF, and CBF and MMSE to identify brain targets contributing to cognitive impairment in AD patients. Finally, a mediation analysis was applied to test the causal pathways among atrophied GMV, hypoperfusion, and cognitive impairment in AD.
Results
Voxel-wise permutation test identified that the left middle temporal gyrus (MTG) had both decreased GMV and CBF in the AD. Moreover, the GMV of this region was positively correlated with MMSE and its CBF, and CBF of this region was also positively correlated with MMSE in AD ( p < 0.05, corrected). Finally, mediation analysis revealed that gray matter atrophy of left MTG drives cognitive impairment of AD via the mediation of CBF (proportion of mediation = 55.82%, β = 0.242, 95% confidence interval by bias-corrected and accelerated bootstrap: 0.082 to 0.530).
Conclusion
Our findings indicated suggested that left MTG is an important hub linking gray matter atrophy, hypoperfusion, and cognitive impairment for AD, and might be a potential treatment target for AD.
Background
Reduced cerebral blood flow (CBF) contributes to the pathophysiology of Alzheimer’s disease (AD). However, it is unclear whether there is a spatial-temporal-specific pattern of changed CBF in AD progression.
Methods
We systematically screened literature databases for cross-sectional and longitudinal studies reporting resting CBF or CBF velocity (CBFv) among patients with AD, mild cognitive impairment (MCI), and healthy controls (HCs). Standardised mean differences (SMDs) for CBF and mean differences (MDs) for CBFv were calculated. Quality assessments, meta-analysis, subgroup analysis, and meta-regression were subsequently performed (PROSPERO: CRD42020207548).
Results
Overall, 244 studies comprising 13,644 participants and 60 regions were included. Compared with HCs, AD subjects had decreased resting CBF throughout the brain (SMD range: -1.87 to -0.32), especially within the posterior cingulate and temporal-parietal regions. However, MCI subjects presented decreased CBF in ten regions with modest effects (SMD range: -0.86 to -0.25), especially in the precuneus. We identified the decreased CBF in the temporal, parietal, and hippocampal regions was associated with the lower AD Mini-Mental State Examination scores.
Conclusions
Our findings suggest that the spatial-temporal pattern of CBF decreased from the precuneus, posterior cingulate and temporal-parietal regions to broader areas with progression from HC to MCI to AD, supporting the incorporation of CBF into the AD research framework.
Neurodegenerative diseases (ND) are of vast origin which are characterized by gradual progressive loss of neurons in the brain region. ND can be classified according to the clinical symptoms present (e.g. Cognitive decline, hyperkinetic, and hypokinetic movements disorder) or by the pathological protein deposited (e.g., Amyloid, tau, Alpha-synuclein, TDP-43). Alzheimer’s disease preceded by Parkinson’s is the most prevalent form of ND world-wide. Multiple factors like aging, genetic mutations, environmental factors, gut microbiota, blood-brain barrier microvascular complication, etc. may increase the predisposition towards ND. Genetic mutation is a major contributor in increasing the susceptibility towards ND, the concept of one disease-one gene is obsolete and now multiple genes are considered to be involved in causing one particular disease. Also, the involvement of multiple pathological mechanisms like oxidative stress, neuroinflammation, mitochondrial dysfunction, etc. contributes to the complexity and makes them difficult to be treated by traditional mono-targeted ligands. In this aspect, the Poly-pharmacological drug approach which targets multiple pathological pathways at the same time provides the best way to treat such complex networked CNS diseases. In this review, we have provided an overview of ND and their pathological origin, along with a brief description of various genes associated with multiple diseases like Alzheimer’s, Parkinson’s, Multiple sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Huntington’s and a comprehensive detail about the Poly-pharmacology approach (MTDLs and Fixed-dose combinations) along with their merits over the traditional single-targeted drug is provided. This review also provides insights into current repurposing strategies along with its regulatory considerations.
Given the significant societal challenges posed by Alzheimer's disease (AD), there is an urgent need to speed up the drug discovery process for this devastating neurodegenerative disease. The development of repurposed medications that have marketing authorization and a proven safety profile is a highly desirable approach. There is growing evidence that certain antihypertensive compounds may be protective, not just acting against vascular dementia, but also having benefits in AD. One antihypertensive currently being assessed for repurposing for AD is nilvadipine, a dihydropyridine (DHP) calcium channel antagonist. Animal studies have shown that nilvadipine decreases amyloid burden in transgenic mouse models of AD and early clinical studies have indicated a favorable safety profile for nilvadipine in AD patients. Based on the positive preclinical and clinical studies, a phase III trial of nilvadipine is currently being conducted across 23 clinical sites in 9 European countries (www. nilvad.eu) to determine the safety and efficacy of this medication in mild to moderate AD.
The spleen tyrosine kinase (Syk) is a well known mediator of inflammatory responses in immune cells. It has been suggested that Syk mediates Aβ-induced microglial activation in vitro but this phenomenon has never been investigated in vivo. Using transgenic mouse models of Alzheimer's disease (AD) overexpressing Aβ peptides (Tg PS1/APPsw and Tg APPsw) and wild-type littermates, we assessed the immunolocalization of activated Syk (phosphorylated Syk at Tyr 525/526) by confocal microscopy. Our high-resolution confocal microscopy study demonstrates an upregulation of phosphorylated Syk (p-Syk) in cortical microglia and in particular, in amoeboid microglia in the brain of Tg APPsw and Tg PS1/APPsw compared to wild-type littermates, suggesting that Syk plays a role in microglial activation in vivo. Dystrophic neurites in the vicinity of β-amyloid deposits show an upregulation of phosphorylated/activated Syk suggesting that Syk may contribute to the degeneration of neurites. Interestingly, astrocytes are not immunopositive for activated Syk showing that Syk expression in the CNS is mainly localized to neurons and microglia. In summary, our data support a functional role of Syk in microglial activation and suggest an involvement of Syk in the degeneration of neurites around β-amyloid deposits supporting the involvement of Syk in the pathological processes associated with AD.
Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.
Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.
Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.
Vascular dementia (VaD)--secondary to cerebrovascular disease (CVD)--has been traditionally distinguished from Alzheimer's disease (AD), which is a purely neurodegenerative form of dementia. However, CVDs such as lacunes and white matter lesions are common in patients with AD, whereas certain pathological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice. This article provides an overview of MD, including the incidence, diagnosis, and treatment. In particular, we emphasize that functional brain imaging, including perfusion single photon emission computed tomography and benzodiazepine receptor binding measurement, in combination with morphological imaging (such as magnetic resonance imaging) is useful for distinguishing AD, VaD and MD. In addition to antiplatelet medications, cholinesterase inhibitors and N-methyl-D-aspartic acid antagonists may be effective in treating MD. Moreover the vascular risk factors also should be treated appropriately. The article describes the need for further studies to develop a better understanding of MD.
A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats.
Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats.
A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect.
Recent studies have shown that some antihypertensive medications are associated with a significant reduction in the incidence of Alzheimer's disease (AD). However, it remains uncertain whether antihypertensive drugs may have a preventive effect on cognitive decline in patients with AD. We investigated the effects of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor γ-stimulating activity, on cognition and regional cerebral blood flow (rCBF) in elderly hypertensive patients with AD.
A total of 20 patients with probable AD and essential hypertension were randomly assigned to the telmisartan group (n = 10, 40-80 mg daily) or the amlodipine group (n = 10, 5-10 mg daily) for 6 months.
The groups had a similar significant reduction in systolic and diastolic blood pressure after treatment. The telmisartan group did not show any changes in cognitive function test scores, while the amlodipine group showed significantly higher scores on the AD Assessment Scale-Cognitive Subscale (Japanese version). Analysis of covariance to analyze treatment effect revealed that the telmisartan group showed increased rCBF in the right supramarginal gyrus, superior parietal lobule, cuneus, and lingual gyrus compared with the amlodipine group, while the amlodipine group showed increased rCBF only in the right cingulate gyrus compared with the telmisartan group at 6 months.
These findings suggest that telmisartan may have additional benefits and be useful for the treatment of elderly hypertensive patients with AD.
Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of an ageing population worldwide, the incidence of dementia is expected to rise exponentially over the coming decades. Vascular risk factors are implicated in the pathogenesis of both AD and VaD. Hypertension in midlife is particularly associated with an increased risk of developing dementia. One might hope the treatment of high blood pressure in midlife would reduce the risk of developing dementia, as it does the risk of stroke. Divergent results have been reported in studies examining this effect, with the evidence suggesting that certain antihypertensives confer benefits beyond others. This implies that certain drugs may have neuroprotective properties separate to their blood pressure lowering capabilities. Recent trials have added to our understanding of these relationships.
A 76-year-old man was referred to our hospital because of memory impairment. He was diagnosed as having early Alzheimer's disease, in addition to hypertension and type II diabetes mellitus. Nilvadipine (a Ca-channel blocker), telmisartan (an angiotension II receptor blocker), and pioglitazone (an insulin sensitizer) were administered for the control of the hypertension and diabetes. After 6 months of treatment, the scores on verbal fluency (animals and vegetables/60 seconds) and frontal assessment battery of the patient improved despite no significant changes on the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. Moreover, follow-up examination of SPECT demonstrated an improvement of cerebral perfusion in the frontal and temporoparietal regions. In addition to nilvadipine, a highly lipophilic Ca channel antagonist agent that easily penetrates the central nervous system, PPARgamma agonists, such as pioglitazone and termisartan, may have had favourable effects on cognitive function and cerebral perfusion in this patient.
To study the 3-year effect of oral nilvadipine, a calcium antagonist, on visual field performance and ocular circulation in open-angle glaucoma (OAG) with low-normal intraocular pressure (IOP).
A randomized, placebo-controlled, double-masked, single-center trial.
Patients with OAG who were younger than 65 years and had untreated IOP consistently of 16 mmHg or less.
Oral nilvadipine (2 mg twice daily) or placebo was assigned randomly to patients fulfilling the criteria by the minimization method of balancing the groups according to age, refraction, and the mean deviation (MD) value (Humphrey Perimeter 30-2 SITA Standard Program; Humphrey Instruments, Inc., San Leandro, CA) of the eye with less negative MD. No topical ocular hypotensive drugs were prescribed. Visual field testing was performed every 3 months; fundus examination and IOP, blood pressure, and pulse rate measurements were carried out every month; and quantitative indexes of circulation in the optic disc rim (NB(ONH)) and choroid in the foveal area (NB(fovea)) were determined using the laser speckle method at 0, 3, 6, 12, 18, 24, 30, and 36 months.
The time courses of MD, NB(ONH), and NB(fovea) in the eye with less negative MD.
Thirty-three patients were enrolled; 17 were assigned to nilvadipine and 16 were assigned to placebo; 13 in each group completed the study. No significant intergroup difference was seen in age, refraction, or baseline values of any of the parameters. During the 3-year period, the IOP averaged 12.6 mmHg in the nilvadipine group and 12.8 mmHg in the placebo group (P>0.1), and no significant change from baseline or intergroup difference was seen in blood pressure or pulse rate. The estimated slope of change in the MD was less negative in the nilvadipine than in the placebo group (-0.01 vs. -0.27 decibels/year; P = 0.040). The NB(ONH) and NB(fovea) values remained increased compared with baseline for the study period by approximately 30% to 40% only in the nilvadipine group, and the intergroup difference was significant (P = 0.003 for NB(ONH) and P = 0.007 for NB(fovea)).
Nilvadipine (2 mg twice daily) slightly slowed the visual field progression and maintained the optic disc rim, and the posterior choroidal circulation increased over 3 years in patients with OAG with low-normal IOP.
Freshly solubilized β-amyloid (Aβ) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that Aβ vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase A2 (PLA2), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA2, and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for Aβ vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce Aβ, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized Aβ peptides can trigger a pro-inflammatory reaction in the vasculature that can be blocked by inhibiting specific target molecules, providing the basis for novel therapeutic intervention.
We compared haemodynamic and humoral responses to nifedipine and nilvadipine in 25 elderly hypertensives. The study had a single-blind crossover design. Doppler flowmetry and laboratory examinations were performed before and after nifedipine and nilvadipine. Both nifedipine and nilvadipine significantly reduced mean arterial pressure to the same extent. Nilvadipine increased cardiac output, carotid flow and vertebral flow whereas nifedipine had no significant effect on either cardiac output or regional blood flows. Nilvadipine increased plasma atrial natriuretic peptide and decreased plasma noradrenaline. In the nilvadipine group, the relations between changes in these humoral parameters and those in cardiac output suggest that an elevation of pre-load may play a role in increasing cardiac output. The effects of nilvadipine on cerebral perfusion might provide additional benefits for the elderly hypertensives.
To improve the diagnostic performance of PET as an aid in evaluating patients suspected of having Alzheimer's disease, we developed a fully automated method which generates comprehensive image presentations and objective diagnostic indices.
Fluorine-18-fluorodeoxyglucose PET image sets were collected from 37 patients with probable Alzheimer's disease (including questionable and mild dementia), 22 normal subjects and 5 patients with cerebrovascular disease. Following stereotactic anatomic standardization, metabolic activity on an individual's PET image set was extracted to a set of predefined surface pixels (three-dimensional stereotactic surface projection, 3D-SSP), which was used in the subsequent analysis. A normal database was created by averaging extracted datasets of the normal subjects. Patients' datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspections. Diagnostic indices were then generated based on averaged Z-scores for the association cortices.
Patterns and severities of metabolic reduction in patients with probable Alzheimer's disease were seen in the standard 3D-SSP views of extracted raw data and statistical Z-scores. When discriminating patients with probable Alzheimer's disease from normal subjects, diagnostic indices of the parietal association cortex and unilaterally averaged parietal-temporal-frontal cortex showed sensitivities of 95% and 97%, respectively, with a specificity of 100%. Neither index yielded false-positive results for cerebrovascular disease.
3D-SSP enables quantitative data extraction and reliable localization of metabolic abnormalities by means of stereotactic coordinates. The proposed method is a promising approach for interpreting functional brain PET scans.
An automated method was proposed for anatomic standardization of PET scans in three dimensions, which enabled objective intersubject and cross-group comparisons of functional brain images.
The method involved linear scaling to correct an individual brain size and nonlinear warping to minimize regional anatomic variations among subjects. In the linear-scaling step, the anteroposterior length and width of the brain were measured on the PET images, and the brain height was estimated by a contour-matching procedure using the midsagittal plane. In the nonlinear warping step, individual gray matter locations were matched with those of a standard brain by maximizing correlation coefficients of regional profile curves determined between predefined stretching centers (predominantly in white matter) and the gray matter landmarks.
The accuracy of the brain height estimation was compared with skull x-ray estimations, showing comparable accuracy and better reproducibility. Linear-scaling and nonlinear warping methods were validated using [18F]fluorodeoxyglucose and [15O]water images. Regional anatomic variability on the glucose images was reduced markedly. The statistical significance of activation foci in paired water images was improved in both vibratory and visual activation paradigms. A group versus group comparison following the proposed anatomic standardization revealed highly significant glucose metabolic alterations in the brains of patients with Alzheimer's disease compared with those of a normal control group.
These results suggested that the method is well suited to both research and clinical settings and can facilitate pixel-by-pixel comparisons of PET images.
Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.
To characterize clinically subjects with MCI cross-sectionally and longitudinally.
A prospective, longitudinal inception cohort.
General community clinic.
A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.
The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively.
The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.
Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.
The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.
After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation.
To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia.
Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs.
Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33).
The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.
High blood pressure and stroke are associated with increased risks of dementia and cognitive impairment. This study aimed to determine whether blood pressure lowering would reduce the risks of dementia and cognitive decline among individuals with cerebrovascular disease.
The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind, placebo-controlled trial conducted among 6105 people with prior stroke or transient ischemic attack. Participants were assigned to either active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcomes for these analyses were dementia (using DSM-IV criteria) and cognitive decline (a decline of 3 or more points in the Mini-Mental State Examination score).
During a mean follow-up of 3.9 years, dementia was documented in 193 (6.3%) of the 3051 randomized participants in the actively treated group and 217 (7.1%) of the 3054 randomized participants in the placebo group (relative risk reduction, 12% [95% confidence interval, -8% to 28%]; P =.2). Cognitive decline occurred in 9.1% of the actively treated group and 11.0% of the placebo group (risk reduction, 19% [95% confidence interval, 4% to 32%]; P =.01). The risks of the composite outcomes of dementia with recurrent stroke and of cognitive decline with recurrent stroke were reduced by 34% (95% confidence interval, 3% to 55%) (P =.03) and 45% (95% confidence interval, 21% to 61%) (P<.001), respectively, with no clear effect on either dementia or cognitive decline in the absence of recurrent stroke.
Active treatment was associated with reduced risks of dementia and cognitive decline associated with recurrent stroke. These findings further support the recommendation that blood pressure lowering with perindopril and indapamide therapy be considered for all patients with cerebrovascular disease.
Through visual assessment by three-dimensional (3D) brain image analysis methods using stereotactic brain coordinates system, such as three-dimensional stereotactic surface projections and statistical parametric mapping, it is difficult to quantitatively assess anatomical information and the range of extent of an abnormal region. In this study, we devised a method to quantitatively assess local abnormal findings by segmenting a brain map according to anatomical structure. Through quantitative local abnormality assessment using this method, we studied the characteristics of distribution of reduced blood flow in cases with dementia of the Alzheimer type (DAT). Using twenty-five cases with DAT (mean age, 68.9 years old), all of whom were diagnosed as probable Alzheimer's disease based on NINCDS-ADRDA, we collected I-123 iodoamphetamine SPECT data. A 3D brain map using the 3D-SSP program was compared with the data of 20 cases in the control group, who age-matched the subject cases. To study local abnormalities on the 3D images, we divided the whole brain into 24 segments based on anatomical classification. We assessed the extent of an abnormal region in each segment (rate of the coordinates with a Z-value that exceeds the threshold value, in all coordinates within a segment), and severity (average Z-value of the coordinates with a Z-value that exceeds the threshold value). This method clarified orientation and expansion of reduced accumulation, through classifying stereotactic brain coordinates according to the anatomical structure. This method was considered useful for quantitatively grasping distribution abnormalities in the brain and changes in abnormality distribution.
We investigated the effects of nilvadipine and amlodipine on the cerebral ischemia-induced impairment of spatial memory in 8-arm radial maze performance and hippocampal CA1 apoptosis in rats. Single cerebral ischemia impaired memory without inducing apoptosis. In these rats, neither nilvadipine nor amlodipine at 3.2 mg/kg, i.p. improved the impaired memory. On the other hand, repeated cerebral ischemia (10 min ischemia x 2, 1 h interval) impaired spatial memory and induced hippocampal apoptosis 7 days after the final occlusion/reperfusion. Moreover, repeated ischemia increased the apoptotic cell number, an effect observed after 3 days and peaked after 7 days. However, mRNA expression of the apoptosis-related early oncogene bax and CPP 32 (caspase-3) was observed after 24 h. In these rats, nilvadipine, but not amlodipine, significantly improved memory, concomitantly decreased hippocampal apoptosis, and suppressed both bax and CPP 32 expression. These results suggest that nilvadipine improved the memory impairment in repeated ischemia by reducing bax and CPP 32 expression and suppressing the induction of apoptosis in the hippocampus. Nilvadipine may have a neuroprotective effect and could be a useful pharmacotherapeutic agent for cerebrovascular dementia.
Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.
In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.
A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.
Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.
The development of Alzheimer's disease (AD) is generally thought to correlate with cerebral accumulation of Abeta. It has previously been shown that Abeta peptides enhance vasoconstriction in isolated arteries and oppose certain vasorelaxants. Moreover, exogenous application of Abeta peptides causes cerebral vasoconstriction in rodents and in transgenic mouse models of AD that overexpress Abeta there is reduced cerebral blood flow. In the present study, we investigated the effect of nilvadipine, a dihydropyridine-type calcium channel blocker, on Abeta induced vasoconstriction in isolated arteries and in vivo on cerebral blood flow (CBF) of an AD transgenic mouse model overexpressing Abeta (Tg APPsw line 2576). Nilvadipine completely inhibited the vasoactivity elicited by Abeta in rat aortae and in human middle cerebral arteries. The effect of a short treatment duration (2 weeks) with nilvadipine on regional CBF was investigated in 13-month-old Tg APPsw mice and control littermates using a laser Doppler imager. Additionally, CBF was also measured in 20-month-old Tg APPsw mice and control littermates that were chronically treated with nilvadipine for 7 months. Untreated Tg APPsw mice showed a reduction of regional CBF compared to their untreated control littermates. Nilvadipine restored cortical perfusion levels in Tg APPsw to values similar to those observed in control littermates without notably affecting the CBF of control mice. All together, these data suggest that nilvadipine might be useful for the treatment of oligemia associated with AD.
To evaluate the effect of a calcium antagonist, nilvadipine, on cerebral blood flow and oxygen metabolism, we prospectively examined five ischaemic stroke patients, with both hypertension and chronic major cerebral artery occlusion, using positron emission tomography. The blood pressure showed a significant decrease after 3 months of nilvadipine treatment, the cerebral blood flow in the affected regions showed a significant increase and the oxygen extraction fraction showed a significant decrease. We conclude that nilvadipine is a safe and effective anti-hypertensive agent for patients with both hypertension and chronic major cerebral artery occlusion.
Background
Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective
To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design
A prospective, longitudinal inception cohort.Setting
General community clinic.Participants
A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures
The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results
The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions
Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
The results of both in vitro and animal studies suggest that calcium dysregulation plays an important role in neuronal cell degeneration, and thus support the use of calcium antagonists for the treatment of Alzheimer’s disease (AD). The aim of this pooled analysis of 2 multicentre randomised trials was to assess the efficacy and tolerability of nimodipine administered for 6 months in a total of 1648 patients with probable AD. There were no statistically significant differences between nimodipine and placebo for any of the primary outcome variables. However, significant improvements in the secondary variable, Mini Mental State Examination (MMSE; p = 0.004) score, compared with the placebo group, were noted when the individual study data were pooled. Differences favouring nimodipine also emerged when patients were stratified according to their baseline MMSE scores. In more severely impaired patients (MMSE scores 12 to 18), nimodipine 180 mg/day was significantly superior to placebo for Alzheimer’s Disease Assessment Scale (ADAS) total (p = 0.01) and cognitive (p = 0.035) scores as well as MMSE total score (p = 0.006). Secondary analyses of these data indicated that patients with more severe cognitive disturbances, yet able to recall ≥ 1 word twice in succession (BSR test), demonstrated the greatest response to nimodipine 180 mg/day treatment. Nimodipine was well tolerated when administered at either 90 or 180 mg/day.
In conclusion, although nimodipine did not significantly slow disease progression in the overall study population, patients with moderately severe dementia did appear to benefit from nimodipine treatment, especially those who performed well on the selective reminding test.
Deposit of β-amyloid protein (Aβ) in Alzheimer's disease brain may contribute to the associated neurodegeneration. We have studied the neurotoxicity of Aβ in primary cultures of murine cortical neurons, with the aim of identifying pharmacologic ways of attenuating the injury. Exposure of cultures to Aβ (25–35 fragment; 3–25 4mUM) generally triggers slow, concentration-dependent neurodegeneration (over 24–72 h). With submaximal Aβ- (25–35) exposure (10 μM), substantial (>40% within 48 h) degeneration often occurs and is markedly attenuated by the presence of the Ca2+ channel blockers nimodipine (1–20 μM) and Co2+ (100 μM) during the Aβ exposure. However, Aβ neurotoxicity is not affected by the presence of glutamate receptor antagonists. We suggest that Ca2+ influx through voltage-gated Ca2+ channels may contribute to Aβ-induced neuronal injury and that nimodipine and Co2+, by attenuating such influx, are able to attenuate Aβ neurotoxicity.
The effects of an intravenous injection of the novel calcium channel blocker, nilvadipine, on the relative regional cerebral blood flow and relative regional skin blood flow were studied in anesthetized cats using the laser-Doppler method. The effects of nilvadipine were compared with those of nicardipine hydrochloride (nicardipine). Nilvadipine and nicardipine both increased the relative regional cerebral blood flow dose-dependently, in spite of their hypotensive effect. At a dose of 32 micrograms/kg, nilvadipine and nicardipine increased the relative regional cerebral blood flow by 61 +/- 8% and 25 +/- 10% of the predrug value, respectively, 15 min after administration. At this time, both drugs induced a comparable degree of hypotension: -18 +/- 3% of the predrug value for nilvadipine and -25 +/- 2% for nicardipine. After nilvadipine, the relative regional cerebral blood flow enhanced by 45 +/- 10% 180 min after drug administration, whereas after nicardipine, it returned to the predrug value within 60 min. In contrast, the increase in relative regional skin blood flow produced by nilvadipine (32 micrograms/kg) and nicardipine (32 micrograms/kg) was 23 +/- 15% and 32 +/- 8% of the predrug value, respectively, 5 min after drug administration. The effect of nicardipine on the relative regional skin blood flow, compared with that of control, was significantly higher. These results indicate that nilvadipine exhibits a pronounced and longer-lasting effect on the relative regional cerebral blood flow, compared with the relative regional skin blood flow, and that its action on the relative regional cerebral blood flow is more potent than that of nicardipine.
The effects of two dihydropyridine type calcium entry blockers, nilvadipine and nicardipine hydrochloride (nicardipine), on the liberation of free fatty acids (FFAs) were investigated using an experimental model of global cerebral ischemia in rats, and were compared with their pharmacokinetic properties. Nilvadipine, but not nicardipine, at a dose of 100 micrograms/kg i.v., significantly attenuated the liberation of FFAs, particularly docosahexaenoic and arachidonic acid. Furthermore, the brain concentration of nilvadipine was higher than that of nicardipine after equivalent dosing. The results of the present study demonstrate that pharmacokinetic differences between these two calcium entry blockers might explain the difference in their pharmacological efficacy.
1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)
1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of 14C-nilvadipine. 2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4-3.5% in rats and 10.4-22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8-10 h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs. 3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys. 4. With both routes of dosing, urinary excretion of radioactivity was 21-24% dose in rats and 56-61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.
We compared the cardiovascular effect of FR34235, a new dihydropyridine derivative, with the effects of nifedipine, nicardipine, and diltiazem on the dog using in vitro and in vivo preparations. FR34235 reduced the amplitude of coronary arterial contraction induced by K+ more so than that induced by norepinephrine in in vitro preparations. The ID50 values of FR34235 for various arterial strips contracted by K+ were smaller (1/5-1/426) than those of nifedipine and diltiazem, and almost the same as those of nicardipine. There was a greater increase in both the coronary and vertebral blood flow than in the other peripheral arterial flow in anesthetized dogs administered FR34235 (0.32-100 micrograms/kg i.v.), and the duration of effect was about two to three times longer than that of the other drugs. To obtain a vasodilating effect by the intraduodenal route, 10-30 times the intravenous dose of FR34235 was required, far lower than that required of nicardipine. In atrioventricular (AV) and sinoatrial node preparations, FR34235 was weaker in impairing AV conduction than nifedipine, in spite of their similar potencies in increasing coronary flow and decreasing sinus rate. FR34235 was more potent than diltiazem in increasing coronary flow, in spite of their similar potencies on AV conduction. It is concluded that FR34235 has: (a) potent vasodilating activity, probably due to inhibition of Ca2+ influx into the cells; (b) selective and long-lasting effects on the coronary and cerebral arteries in vivo; (c) a wide difference between doses that cause vasodilation and an impairing effect on AV conducting tissues; and (d) therapeutic effects after absorption from the intestinal tract.
Accurate clinical staging of dementia in older subjects has not previously been achieved despite the use of such methods as psychometric testing, behavioural rating, and various combinations of simpler psychometric and behavioural evaluations. The Clinical Dementia Rating (CRD), a global rating device, was developed for a prospective study of mild senile dementia--Alzheimer type (SDAT). Reliability, validity, and correlational data are discussed. The CRD was found to distinguish unambiguously among older subjects with a wide range of cognitive function, from healthy to severely impaired.
Deposit of beta-amyloid protein (A beta) in Alzheimer's disease brain may contribute to the associated neurodegeneration. We have studied the neurotoxicity of A beta in primary cultures of murine cortical neurons, with the aim of identifying pharmacologic ways of attenuating the injury. Exposure of cultures to A beta (25-35 fragment; 3-25 microM) generally triggers slow, concentration-dependent neurodegeneration (over 24-72 h). With submaximal A beta-(25-35) exposure (10 microM), substantial (> 40% within 48 h) degeneration often occurs and is markedly attenuated by the presence of the Ca2+ channel blockers nimodipine (1-20 microM) and Co2+ (100 microM) during the A beta exposure. However, A beta neurotoxicity is not affected by the presence of glutamate receptor antagonists. We suggest that Ca2+ influx through voltage-gated Ca2+ channels may contribute to A beta-induced neuronal injury and that nimodipine and Co2+, by attenuating such influx, are able to attenuate A beta neurotoxicity.
Vascular causes of dementia may be more common than supposed. Vascular factors may also have a role in late-onset Alzheimer's disease, but the role of hypertension in the development of dementia is unclear.
As part of the Longitudinal Population Study of 70-year-olds in Göteborg, Sweden, we analysed the relation between blood pressure and the development of dementia in the age intervals 70-75, 75-79, and 79-85 years in those non-demented at age 70 (n = 382). The sample was followed up for 15 years and examined repeatedly with a comprehensive investigation, including a psychiatric and physical examination. a
Participants who developed dementia at age 79-85 had higher systolic blood pressure at age 70 (mean 178 vs 164 mm Hg, p = 0.034) and higher diastolic blood pressure at ages 70 (101 vs 92, p = 0.004) and 75 (97 vs 90, p = 0.022) than those who did not develop dementia. For subtypes of dementia, higher diastolic blood pressure was recorded at age 70 (101, p = 0.019) for those developing Alzheimer's disease and at age 75 (101, p = 0.015) for those developing vascular dementia than for those who did not develop dementia. Participants with white-matter lesions on computed tomography at age 85 had higher blood pressure at age 70 than those without such lesions. Blood pressure declined in the years before dementia onset and was then similar to or lower than that in non-demented individuals.
Previously increased blood pressure may increase the risk for dementia by inducing small-vessel disease and white-matter lesions. To what extent the decline in blood pressure before dementia onset is a consequence or a cause of the brain disease remains to be elucidated.
The effects of the L-type calcium channel blockers, nicardipine, nimodipine, nilvadipine and amlodipine, on brain dysfunction were examined in senescence-accelerated-prone mice. A disturbed brain function in passive avoidance response, forced swimming, rota-rod and traction tests was observed in senescence-accelerated-prone mice compared to senescence-accelerated-resistant mice. A single oral administration of the four calcium channel blockers tested had little effect on the brain dysfunction in senescence-accelerated-prone mice. In contrast, the daily oral administration of nicardipine (1 and 3 mg/kg), nimodipine (3 mg/kg) and nilvadipine (3 mg/kg), once a day for three weeks, prolonged the shortened latency of step-through in the passive avoidance response and falling time in rota-rod tests. Brain dysfunction in forced swimming and traction tests was not influenced by repeated administration of these blockers. Repeated administration of amlodipine for three weeks in senescence-accelerated-prone mice showed little pharmacological actions in all four tests. Thus, we found that repeated administration of nicardipine, nimodipine and nilvadipine ameliorated the brain dysfunction in these mice. Furthermore, the present study suggests that senescence-accelerated-prone mice can be used as an appropriate model for evaluating the pharmacological effects of calcium channel blockers on brain dysfunction.
Aim:
The brain is sensitive to hypertension, which causes a variety of vascular and neuronal cerebral changes. The present study was designed to assess the effect of long-term treatment with the Ca2+ channel blocker nicardipine on intracerebral (intraparenchymal) arteries in spontaneously hypertensive rats (SHR) by using microanatomical techniques associated with image analysis. The effects of hypertension and treatment with nicardipine on nerve cells and glial fibrillary acid protein (GFAP)-immunoreactive glial cells were also evaluated.
Effects of nicardipine on blood pressure:
In SHR a significant increase in systolic blood pressure in comparison with age-matched normotensive Wistar-Kyoto (WKY) rats was noticeable. Treatment with nicardipine significantly reduced systolic pressure in the SHR. The media: lumen ratio and the thickness of the tunica media were increased in medium (diameter between 150 and 50 microns and small (diameter < 50 microns intracerebral arteries. This phenomenon was accompanied by luminal narrowing. Treatment with nicardipine significantly reduced the thickness of the tunica media, the media: lumen ratio and increased the luminal area, primarily at the level of small pial arteries and of intracerebral arteries.
Effects of nicardipine in the brain:
In control SHR, the number of neurones in the frontal and occipital cortex was reduced in comparison with normotensive WKY rats. GFAP-immunoreactive astrocytes were increased in number (hyperplasia) and in size (hypertrophy), both in the frontal cortex and in the occipital cortex of control SHR. In the CA1, field of the hippocampus, the number of neurones and their size were decreased in SHR in comparison with normotensive WKY rats. Hyperplasia of GFAP-immunoreactive astrocytes of white matter and hypertrophy of those of grey matter was also noticeable. No important changes were found in other portions of the hippocampus. Treatment with nicardipine increased the number of neurones in the frontal cortex and in the occipital cortex of SHR and countered hyperplasia and hypertrophy of GFAP-immunoreactive astrocytes. Moreover, it increased the number of neurones in the CA1 field of the hippocampus and decreased the number and the size of astrocytes of the white matter and grey matter, respectively.
Conclusions:
These findings show that treatment of SHR with nicardipine significantly reduced systolic blood pressure and induced moderate vasodilation of both extracerebral and intracerebral arteries regulating cerebrovascular resistance. The compound also countered some microanatomical changes occurring in the hypertensive brain. The frontal and occipital (visual) cortex and the CA1 field of the hippocampus were the cerebral areas more sensitive to treatment with nicardipine. This suggests that nicardipine induces moderate cerebrovascular dilation and exerts neuroprotective effects on SHR neurones. The possible relevance of the neuroprotective actions of nicardipine in the hypertensive brain deserves to be evaluated in future studies.
Although at present there is no definitive treatment or cure for Alzheimer’s disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer’s disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer’s disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer’s disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing.
The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of β-amyloid and/or to inhibit β-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/β-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an ‘electron trapper’ and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation.
Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer’s disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer’s disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer’s disease.
Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial, investigated whether antihypertensive drug treatment could reduce the incidence of dementia.
Eligible patients had no dementia, were at least 60 years old, and had a blood pressure when seated of 160-219 mm Hg systolic and below 95 mm Hg diastolic. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both drugs, titrated or combined to reduce the systolic blood pressure by at least 20 mm Hg to reach a value below 150 mm Hg. Cognitive function was assessed by the mini mental state examination (MMSE). If the MMSE score was 23 or less, diagnostic tests for dementia were done (DSM-III-R criteria). The cause of dementia was established by the modified ischaemic score with brain imaging or the Hachinski score.
Median follow-up by intention to treat was 2.0 years. Compared with placebo (n=1180), active treatment (n=1238) reduced the incidence of dementia by 50% from 7.7 to 3.8 cases per 1000 patient-years (21 vs 11 patients, p=0.05). The median MMSE score at randomisation was 29 in both treatment groups. At the last available assessment, systolic and diastolic blood pressure were, respectively, 8.3 mm Hg and 3.8 mm Hg lower (p<0.001) in the active-treatment group, but on average the MMSE scores did not change in either group. In the control patients, however, the MMSE decreased (p=0.04) with decreasing diastolic blood pressure, whereas in the active-treatment group MMSE scores improved slightly (p=0.01) with greater reduction in diastolic blood pressure (p=0.002 for between-group difference).
In elderly people with isolated systolic hypertension, antihypertensive treatment was associated with a lower incidence of dementia. If 1000 hypertensive patients were treated with antihypertensive drugs for 5 years 19 cases of dementia might be prevented.
Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. An increased beta-amyloid (Abeta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized Abeta enhances constriction of cerebral and peripheral vessels. We propose that in vivo the Abeta vasoactive property may contribute to cerebral hypoperfusion of AD patients. To test this hypothesis, we intra-arterially infused freshly solubilized Abeta -40 in rats and observed changes in cerebral blood flow and cerebrovascular resistance using fluorescent microspheres. We found that infusion of Abeta in vivo resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that Abeta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.
Calcium plays a pivotal role in mediating many important biological functions. The intracellular calcium concentration is tightly regulated by a variety of systems and mechanisms. Calcium is sequestered by various organelles such as mitochondria and/or endoplasmic reticulum and extruded across the plasma membrane by energy-dependent transport systems. Different Ca2+-binding proteins are also involved in these processes. Alterations in calcium homeostasis might be critically implicated in brain aging and in the neuropathology of Alzheimer's disease (AD). In fact, one of the postulated mechanisms of beta-amyloid toxicity seems to involve a Ca2+ dysregulation accompanied with enhanced vulnerability to excitotoxic stimuli. Although brain characteristic lesions-plaques and tangles-constitute the hallmarks of AD, accumulated evidence suggests the systemic feature of this disease. Therefore peripheral cell lines may represent a useful approach to explore the cellular pathophysiology of AD, including calcium alterations and associated phenomena.
Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca2+ levels and inhibit cellular oxidative stress may be effective in blocking abnormal neuronal apoptosis. In this study, a spontaneous (also referred to as age-induced) model of apoptosis consisting of rat cerebellar granule cells was used to evaluate the antiapoptotic activities of voltage-sensitive Ca2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10-100 nM), amlodipine attenuated intracellular neuronal Ca2+ increases elicited by KCl depolarization but did not affect Ca2+ changes triggered by N-methyl-D-aspartate receptor activation. Amlodipine also inhibited free radical-induced damage to lipid constituents of the membrane in a dose-dependent manner, independent of Ca2+ channel modulation. In parallel experiments, spontaneous neuronal apoptosis was inhibited in dose- and time-dependent manners by antioxidants (U-78439G, alpha-tocopherol, and melatonin), nitric oxide synthase inhibitors (N-nitro-L-arginine and N-nitro-D-arginine), and a nitric oxide chelator (hemoglobin) in the micromolar range. These results suggest that spontaneous neuronal apoptosis is associated with excessive Ca2+ influx, leading to further intracellular Ca2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage-sensitive Ca2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis.
The development of effective treatments for stroke has focused on two general strategies. The first, thrombolysis, became available in 1996, when the Food and Drug Administration approved alteplase (tissue plasminogen activator) for administration within three hours after the onset of ischemic stroke. The goal of thrombolysis is to restore blood flow by lysing an intraarterial thrombus before brain cells die. The second, neuroprotection, is still in the preclinical pipeline. Its aim is to attenuate the intrinsic vulnerability of brain tissue to ischemia by blocking biochemical cascades that cause secondary injury. Prominent among these cascades is the neurotoxicity induced by the . . .
The prevalence and incidence of degenerative and vascular dementias increase exponentially with age, from 70 years onward. In view of the increasing longevity of humans, both varieties are bound to evolve into a major problem worldwide. According to several longitudinal studies, hypertension appears to predispose individuals to the development of cognitive impairment and ensuing dementia, after a period varying from a few years to several decades. Antihypertensive drug treatment, according to preliminary evidence, may serve to reduce the rates of such events. Such findings await to be confirmed by formal therapeutic trials against a backdrop of "historical" observational sources.
Wirkung von Nilvadipin im 1,1-Diphenyl-2-picrylhydrazyl-(DPPH-)Assay in schwach saurem Medium
Für die Untersuchung der Radikalfänger-Eigenschaften von Substanzen im 1,1-Diphenyl-2-picrylhydrazyl-(DPPH-)As-say wurde ein neues Medium (pH 5,6 durch Zugabe von 0,1 mol Acetat-Puffer, 37 °C, 60 min) geschaffen. Die DPPH-auf-hellende Aktivität von typischen Antioxi-dantien war bei pH 8,0 (nach klassischer DPPH-Assay-Methode gemessener pH der Ethanol-Lösung) allgemein schwächer als bei pH 5,6.
Nilvadipin (CAS 75530-68-6), ein lipo-philer Kalzium-Antagonist, führte bei pH 5,6 zu einer wesentlich stärkeren Aufhellung als bei pH 8,0. Nifedipin (CAS 21829-25-4) und Amlodipin (Amlodipin-besilat, CAS 88150-42-9) zeigten eine leichte Wirkung, während 5 weitere Kal-zium-Antagonisten bei keinem der getesteten pH-Werte (pH 4,4-8,0) zu einer Aufhellung von DPPH führten. Probucol und β-Carotin (Standard-Antioxidans) zeigten nahezu die gleiche aufhellende Wirkung wie Nilvadipin. Captopril, Gluta-thion und Bilirubin waren bei pH 5,6 weniger starke Radikalfänger. Weder bei pH 8,0 noch bei pH 5,6 beeinflußten Superoxid- und Hydroxyl-Radikale per se den DPPH-Test. Damit hat sich gezeigt, daß Nilvadipin nur bei einem pH von ca. 5,6-also in schwach saurer Umgebung, wie sie durch Entzündung und/oder Isch-ämie-Reperfusion entstehen kann - ein wirksamer Radikalfänger ist.
Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ET(B) receptor) is associated with neuronal survival in the brain. In the Alzheimer's disease (AD) brain, accumulation of amyloid beta protein (Abeta) is thought to cause neuronal cell death via apoptosis. In the present study, we investigated effects of ET(B) receptor agonists on Abeta-induced neuronal cell death. In primary cultures of rat cortical neurons, Abeta(25-35) caused neuronal cell death in a concentration- and time-dependent manner. Abeta(25-35)-induced neuronal cell death was accompanied by chromatin condensation and DNA fragmentation, exhibiting apoptotic features. ET-3 and IRL-1620, ET(B) receptor agonists, significantly prevented neurons from undergoing Abeta(25-35)-induced cell death. Prior to cell death, Abeta increased concentration of intracellular Ca(2+) ([Ca(2+)](i)). Nimodipine, an L-type voltage-sensitive Ca(2+) channel (L-VSCC) blocker, suppressed the Abeta-induced Ca(2) influx, and attenuated Abeta-induced neuronal apoptosis. On the other hand, omega-conotoxin GIVA, an N-type VSCC blocker and omega-conotoxin MVIIC and omega-agatoxin IVA, P/Q-type VSCC blockers, had no effect. ET-3 and IRL-1620 significantly blocked Abeta(25-35)-induced Ca(2) influx. Furthermore, BQ788, an ET(B) receptor antagonist, inhibited both an anti-apoptotic effect and an L-VSCC-inactivating effect of ET(B) receptor agonists. In conclusion, ET(B) receptor agonists exhibit a protective effect against neurotoxicity of Abeta. Furthermore, these agonists appear to act as anti-apoptotic factors by blocking of L-VSCCs.
We investigated the effects of the Ca2+ antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca2+ antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30–36-week-old mice. The striatal dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1 h after the last injection of each Ca2+ antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30–36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30–36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30–36-week-old mice.
Verbal fluency tests are commonly used in neurocognitive and mental status examinations in patients with suspected dementia. Inflation of test scores as a result of practice effects may yield false-negative results in test-retest and multidisciplinary settings, particularly among patients with mild cognitive deficits. To address this issue, animal naming was administered twice within a 1-week period to a group of individuals referred for suspected dementia who were ultimately diagnosed with mild cognitive impairment (MCI; amnestic form), probable Alzheimer disease (AD), or no dementia. A 2 x 3 repeated-measures analysis of variance revealed a statistically significant interaction between administration time and group. Post hoc analyses indicated that nondemented controls were the only group to demonstrate a significant practice effect, producing an average of approximately three more animal names at time two. Like patients with a diagnosis of AD, subjects with amnestic MCI failed to benefit from repeated exposure to the animal naming test, and only controls showed an average improvement upon retest. This underscores the cognitive similarity between individuals diagnosed with amnestic MCI and AD and suggests that improvement upon retest may be a diagnostically useful finding.
To evaluate the relationship between antihypertensive treatments and cognitive function in elderly hypertensive patients with memory complaints.
The association between cognitive function and antihypertensive drug therapy was studied in 1241 hypertensive elderly patients with memory complaints attending a geriatric outpatient clinic. Cognitive function was assessed using the Mini Mental State Examination (MMSE) and validated neuropsychological tests (Cognitive Efficiency Profile; CEP). Patients were classified into four categories according to their cognitive status: normal cognitive function, mild cognitive impairment (MCI), Alzheimer's disease (AD) or vascular dementia (VaD).
In this population aged 78 +/- 8 years, with a mean blood pressure of 152 +/- 19/86 +/- 12 mmHg, antihypertensive treatment was prescribed for 57% of patients. After adjustment for age, sex and education, treated hypertensive patients had better cognitive function than untreated patients (MMSE score 23.9 +/- 5.6/30 versus 22.7 +/- 6.4/30, P < 0.001, CEP score 49.1 +/- 24.9/100 versus 45.4 +/- 23.7/100, P < 0.001). This association was observed independently of the cognitive status, both in normal, MCI, AD and VaD hypertensive patients. The odds ratio (OR) for AD was 0.58 [95% confidence interval (CI) 0.42-0.81] in treated compared with untreated hypertensive patients. In patients on antihypertensive therapy, higher cognitive function was observed in patients using calcium antagonists compared with those without calcium antagonists (CEP 52.9 +/- 24.6/100 versus 46.4 +/- 23.4/100, P < 0.001; OR for AD 0.67; 95% CI 0.45-0.99), independently of blood pressure level.
Antihypertensive therapy was associated with a lower risk of cognitive impairment and AD. In particular, the use of calcium antagonists was associated with a decreased risk of cognitive impairment and AD independently of the blood pressure level, suggesting a specific neuroprotective effect of these antihypertensive agents.
To evaluate the effect of a calcium antagonist, nilvadipine, on cerebral blood flow and oxygen metabolism, we prospectively examined five ischaemic stroke patients, with both hypertension and chronic major cerebral artery occlusion, using positron emission tomography. The blood pressure showed a significant decrease after 3 months of nilvadipine treatment, the cerebral blood flow in the affected regions showed a significant increase and the oxygen extraction fraction showed a significant decrease. We conclude that nilvadipine is a safe and effective anti-hypertensive agent for patients with both hypertension and chronic major cerebral artery occlusion.
Mild cognitive impairment. Clinical characterization and outcome
- Petersen
Anatomic standardization: Linear scaling and nonlinear warping of functional brain images
- Minoshima