The Open Neurology Journal




ISSN: 1874-205X ― Volume 13, 2019

The Insertion/Deletion Polymorphism of the Angiotensin Converting Enzyme (ACE) in Parkinson’s Disease



Spiridon Papapetropoulos*, 1, 2, Kostantinos Glynos3, Zongmin Zhou3, Stylianos E Orfanos3, Georgia Mitsi4, Andreas Papapetropoulos5
1 Department of Neurology University of Miami, Miller School of Medicine, USA
2 Department of Neurology, Regional University Hospital of Patras, Greece
3 George P. Livanos-Marianthi Simou Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens School of Medicine, Athens, Greece
4 University of Miami/Humana Health Research Services, USA
5 Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece

Abstract

Parkinson’s disease (PDI is a neurodegenerative disorder of unknown etiology. Both genetic and environmental factors are thought to be implicated to some extent. The ACE gene insertion/deletion (I/D) polymorphism has been associated with common neurodegenerative disorders that share similar clinical and neuropathological features with PD (Alzheimer’s disease). In this study we set out to examine the role of the ACE gene insertion/deletion (I/D) polymorphism in Parkinson’s disease (PD).

We conducted a case-control association study among 77 PD patients and 50 non-PD controls from Greece.

The genotype frequencies for II, ID, and DD were 39, 48, and 13%, respectively, in the PD group and 32, 50, and 18% in the control group. Although the DD frequency was higher in the case group statistical significance was not reached.

We conclude that although disease modifying effects cannot be excluded, the ACE insertion/deletion polymorphism is unlikely to be an important determinant of susceptibility to PD in this population.

Keywords: Angiotensin Converting Enzyme, ACE, Polymorphism, Insertion-deletion, Parkinson’s disease, Association study.


Article Information


Identifiers and Pagination:

Year: 2008
Volume: 2
First Page: 66
Last Page: 70
Publisher Id: TONEUJ-2-66
DOI: 10.2174/1874205X00802010066

Article History:

Received Date: 16/4/2008
Revision Received Date: 17/9/2008
Acceptance Date: 19/9/2008
Electronic publication date: 31/10/2008
Collection year: 2008

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© Papapetropoulos et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Neurology, University of Miami, Miller School of Medicine, Clinical Research Building 1120 N.W. 14th Street, 13th Floor Room 1349, Miami, FL 33136, USA; Tel: (+1)(305) 243-8461/(+1)(305) 243-9620; Fax: (+1)(305) 243-3321; E-mail: spapapetropoulos@med.miami.edu




1. INTRODUCTION

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders characterized by selective neurodegeneration, leading to extrapyramidal, hypokinetic motor dysfunction (tremor, rigidity, bradykinesia). However, parkinsonian disorders may present with the additional atypical features of neuropsychiatric (dementia, depression, psychosis) and autonomic involvement. Pathogenic mutations in at least seven different genes are implicated in parkinsonism highlighting the importance of genetic factors and heterogeneous nature of the syndrome [1Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects Nat Rev Genet 2006; 7(4): 306-18.]. This clinical heterogeneity is also noted with similar characteristics in the presentation of other neurodegenerative disorders like Alzheimer’s disease (AD), which share clinical and pathological characteristics with PD [2Papapetropoulos S, Lieberman A, Gonzalez J, Mash DC. Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease? Acta Neurol Scand 2005; 111(6): 353-9.].

One candidate gene investigated for its relevance in neurodegeneration in both AD [3Kolsch H, Jessen F, Freymann N, et al. ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia Neurosci Lett 2005; 377(1): 37-9., 4Meng Y, Baldwin CT, Bowirrat A, et al. Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community Am J Hum Genet 2006; 78(5): 871-7.] and PD [5Lin JJ, Yueh KC, Chang DC, Lin SZ. Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease J Neurol Sci 2002; 199(1-2): 25-9., 6Mellick GD, Buchanan DD, McCann SJ, et al. The ACE deletion polymorphism is not associated with Parkinson's disease Eur Neurol 1999; 41(2): 103-6.] is the angiotensin-converting enzyme (ACE). ACE increases blood pressure through conversion of angiotensin I (inactive) to the potent vasoconstrictor angiotensin II [7Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists Pharmacol Rev 1993; 45(2): 205-51.]. Moreover, ACE is a major pathway for the degradation of bradykinin [8Atlas SA. The renin-angiotensin system revisited: classical and nonclassical pathway of angiotensin formation Mt Sinai J Med 1998; 65(2): 87-96.], a peptide of the kinin family involved in the regulation of vascular tone that also participates in the peripheral inflammatory response [9Reiser G, Binmoller FJ, Donie F. Mechanisms for activation and subsequent removal of cytosolic Ca2+ in bradykinin-stimulated neuronal and glial cell lines Exp Cell Res 1990; 186(1): 47-53.]. Apart from angiotensin II and bradykinin, endogenously occurring neuro-peptides, like substance P and opioid peptides have been identified as ACE substrates. An insertion/deletion (I/D) polymorphism of the ACE gene [10Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels J Clin Invest 1990; 86(4): 1343-6.] accounting for half the variance in serum ACE levels has been described. We set out to study this ACE gene polymorphism, in a well characterized cohort of PD patients and aged control subjects.

2. MATERIALS AND METHODS

2.1. Study Population

The study population consisted of 77 patients with idiopathic PD and 50 controls. PD patients were consecutively recruited in the Department of Neurology of the Regional University Hospital of Patras, Greece (a tertiary referral center) over a period of 2 years. The controls were randomly selected from patients seen in the Regional University Hospital Evagelismos, Athens, Greece and were identified as healthy (no identifiable medical condition including neurological disorder) by their treating physicians. All PD patients and controls were Caucasians, genetically unrelated and of Greek origin. Informed consent was obtained from all the subjects. Diagnosis of PD was made according to the UK PD Society Brain Bank diagnostic criteria [11Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases J Neurol Neurosurg Psychiatry 1992; 55(3): 181-4.]. Thus, only patients who had bradykinesia and at least two of rigidity, rest tremor and postural instability were included. All patients were investigated with either brain CT or MRI. Cases considered as atypical parkinsonism, vascular parkinsonism, or any PD plus syndrome, were excluded from the study.

During a semi-structured interview demographic data, complete past medical history, age of PD onset, modality of presentation, duration of PD, and dosage of levodopa therapy were collected. The Unified Parkinson's Disease Rating Scale (UPDRS) [12Fahn S, Elton RL. Members of the UPDRS Development Committee Unified Parkinson's Disease Rating Scale In: Fahn S, Marsden CD, Calne DB, Eds. Recent developments in Parkinson's disease. 2nd ed. Florham Park, NJ: Macmillan Health Care Information 1987; pp. 153-64.] was completed during clinical examination and was used for evaluation of disease severity. This includes UPDRS I (mentation, behaviour and mood), UPDRS II (activities of daily living), UPDRS III (motor examination), UPDRS IV (complications of therapy), Hoehn & Yahr scale [13Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality Neurology 1967; 17(5): 427-.] (measures the severity of the disease and is based on lateralization of the symptoms and balance evaluation) and Schwab & England scale [14Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson's disease In: Gillinghm FD, IMl , Eds. Third symposium of Parkinson's disease. Edinburgh: Livingstone 1969; pp. 152-7.] (also measures activities of daily living).

2.2. Laboratory Technique

Genomic DNA was isolated from whole blood using the NucleoSpin Blood L kit (Mecherey – Nagel) following the protocol recommended by the manufacturer. To determine the 287-bp insertion/deletion polymorphism in intron 16 of the ACE gene, a conventional PCR [10Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels J Clin Invest 1990; 86(4): 1343-6.] was performed using 500 ng genomic DNA as template with a flanking primer pair 5’ CTG GAG ACC ACT CCC ATC CTT TCT 3’ and 5’ GAT GTG GCC ATC ACA TTC GTC AGA T-3’ in a solution of 25 μl containing 20 pmol of each primer, 0,5mM dNTP, 2mM Mg, 10mM Tris-HCl (pH 8.8), 50mM KCl, 0.08% Nonidet P40 and 1unit of Taq DNA Polymerase, (Fermentas, Lithuania). Amplification with this primer pair results in 490 bp and 190 bp products corresponding to I and D alleles, respectively. PCR was carried out on the Robo Cycler 96 (Stratagene, USA) with initial denaturation at 94 oC for 10 min, followed by 30 cycles at 94 oC for 1 min, at 58 oC (annealing) for 1 min and at 72 oC (extension) for 1 min and then by a final extension period at 72 oC for 10 min. PCR products were visualised on a 1.5 % agarose-gel containing ethidium bromide. To reduce the incidence of mistyping ID as DD, each DD genotype was subjected to a second run of PCR with a primer pair 5’ TGG GAC CAC AGC GCC CGC CAC TAC 3’ and 5’ TCG CCA GCC CTC CCA TGC CCA TAA 3’ that recognizes the insertion-specific sequence with the following program: 10 min denaturation at 94oC, followed by 30 cycles at 94 oC for 50 seconds, at 62 oC (annealing) for 50 seconds and at 72 oC (extension) for 1 min. Under these conditions, only the I allele produced a 335 bp amplicon. Genotyping was performed in a blinded fashion with respect to clinical status of patients and controls.

2.3. Statistical Analysis

Statistical analysis was performed using the SPSS for Windows release 11.0, run on an IBM-compatible computer. Mann-Whitney U test for two samples was used in non-parametric comparisons of continuous data. Chi-square with Yates’s corrected p-value and 2-tailed Fischer’s exact test were used, as appropriate, for the comparison of proportions. For corrections of associations, multivariate analysis was performed using stepwise logistic regression. Adjustments were made for gender, age at onset and disease stage. The level of statistical significance was set at p<0.05. The study was approved by the local Institutional Review Board (IRB).

3. RESULTS

Our study population consisted of 77 PD patients (43 men and 34 women), age 35 to 89 years with the mean of 69.2 (SD 10.4) years, and 50 control subjects (35 men and 15) women, age 19 to 80 years with the mean of 49.5 (SD 21.6) years. PD patients had a mean age of onset of 62.84 (SD11.30) years (the age at onset of PD was defined as the appearance of the first symptom estimated by medical interview). The mean duration of symptoms was 6.27 (SD 5.28) years.

The ACE I/D polymorphism genotypes and allele frequencies are presented in Table 1. The distribution of II, ID and DD genotypes was not significantly different between PD patients and control subjects (p=0.6). The most frequent genotype was ID. There were fewer II genotypes 10 (13.0%) and more DD genotypes 30 (39.0%) in the PD patients. ACE genotypes for our cohort, PD cases and controls independently, were in Hardy–Weinberg equilibrium. The D and I allele distributions in the PD and control groups also revealed no significant differences (p=0.6). The D alleles were more common in both groups (63.0% in the PD group and 57.0% in the control group). No significant associations were observed when adjustment using stepwise logistic regression was applied (p<0.05).

Table 1

ACE Polymorhisms in Patients with Idiopathic Parkinson’s Disease (PD) and Non-PD Controls




The most predominant symptoms at onset were bradykinesia or rigidity related. At the time of examination, the mean total UPDRS was 51.7 (SD 35.4). The UPDRS subscores were: UPDRSI 6.27 (SD 3.53), UPDRSII 15.82 (SD 11.16), UPDRSII (or UPDRSm) 31.09 (SD 20.79), UPDRSIV 2.52 (SD 3.95). The mean Hoehn & Yahr score was 2.56 (SD 1.14) and mean Swab & England score was 71.30% (SD24.46%). The main symptoms of PD at onset and examination, and the L-dopa induced motor side effects (dyskinesias, wearing-off and on-off phenomena), the vascular comorbid conditions (ischemic heart disease and cerebrovascular disease) and family history of PD patients are presented in Table 2. The subgroup analysis of main PD symptoms and L-dopa motor side effects according to the presence or absence of the DD genotype (Table 2) revealed higher frequency of the DD phenotype in patients with the akinetic-rigid form of the disease and L-dopa induced motor complications. These differences were not statistically significant. When results were analyzed by groups defined by phenotype and not by genotype, a marginally non-significant result was revealed: there were only 9 DD homozygotes (26.5%) in the patients with an initial tremor-dominant form of PD (n=34) compared to 21 DD homozygotes (48.8%) in the bradykinesia-rigidity dominant form (n=43) (Fisher exact test p=0.061 and Pearson χ2 test p=0.061).

Table 2

Subgroup Analys is of Main PD Symptoms and L-Dopa Motor Side Effects According to ACE Genotypes




Finally, we compared the distribution of the genotypes (DD, ID, II) in PD patients and control subjects categorized by age group. For PD patients we used the age of onset (age < 50, 50–59, 60–69 and ≥70 years). No statistically significant differences were noted in the age subgroup analysis although patients with younger onset PD tended to have the DD phenotype more frequently. The results of this analysis are presented in Table 3.

Table 3

Comparison ACE Genotypes in PD Patients and Control Subjects Categorized by Age Group




DISCUSSION

The ACE gene is located on chromosome 17q23 and consists of 26 exons and 25 introns. While ACE is best known for the conversion of angiotensin I to angiotensin II and for the degradation of bradykinin, this dipeptidyl carboxypeptidase has additional substrates. A substrate of special interest with regard to PD is substance P [15Skidgel RA, Defendini R, Erdos EG. Angiotensin I converting enzyme and its role in neuropeptide metabolism In: Turner AJ, Ed. Neuropepetides and their peptidases. New York: Ellis Horwood 1987; pp. 165-82.], an undecapeptide that displays neuroprotective effects [16Chen LW, Yung KK, Chan YS. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease Curr Drug Targets 2004; 5(2): 197-206.-18Barker R. Substance P and Parkinson's disease: a causal relationship? J Theor Biol 1986; 120(3): 353-62.]. Substance P also increases rat locomotor activity when microinjected into discrete regions of the basal ganglia including the substantia nigra reticulata (SNr), substantia nigra compacta (SNc), ventral tegmental area (VTA), and globus pallidum (GP) [19Kalivas PW, Deutch AY, Maggio JE, Mantyh PW, Roth RH. Substance K and substance P in the ventral tegmental area Neurosci Lett 1985; 57(3): 241-6.-22Napier TC, Mitrovic I, Churchill L, Klitenick MA, Lu XY, Kalivas PW. Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P Neuroscience 1995; 69(1): 59-70.]. Several studies in rats have also shown that the substance P can increase dopamine outflow [23Furmidge LJ, Duggan AW, Arbuthnott GW. Substance P release from rat nucleus accumbens and striatum: an in vivo study using antibody microprobes Brain Res 1993; 610(2): 234-41.-27Kemel ML, Desban M, Glowinski J, Gauchy C. Distinct presynaptic control of dopamine release in striosomal and matrix areas of the cat caudate nucleus Proc Natl Acad Sci USA 1989; 86(22): 9006-10.] as well as acetylcholine release [28Anderson JJ, Chase TN, Engber TM. Substance P increases release of acetylcholine in the dorsal striatum of freely moving rats Brain Res 1993; 623(2): 189-94.] under normal conditions.

A deletion/insertion (D/I) polymorphism of ACE has been reported that arises from the presence or absence of a 287-base pair sequence of intron 16 resulting in three genotypes (DD/II homozygotes and ID heterozygote) [29Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1) Nucleic Acids Res 1992; 20(6): 1433.]. Although ACE activity is found in plasma, the majority of the biologically active enzyme is tissue-bound [30Esther CR, Marino EM, Howard TE, et al. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice J Clin Invest 1997; 99(10): 2375-85.]. Tiret et al. [31Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels Am J Hum Genet 1992; 51(1): 197-205.] provided evidence that the insertion/deletion (ID) polymorphism is associated with higher plasma ACE activity. Later reports established that the DD genotype is also associated with a higher tissue ACE activity [32Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism Circulation 1995; 92(6): 1387-8.]. As reduced neuroprotection is implicated in the pathogenesis of PD [33Mandel S, Grunblatt E, Riederer P, Gerlach M, Levites Y, Youdim MB. Neuroprotective strategies in Parkinson's disease : an update on progress CNS Drugs 2003; 17(10): 729-62.], one could speculate that the increased ACE activity in subjects with a DD genotype could lower the levels of substance P, making them more susceptible to PD. Lower levels of substance P may also affect locomotion and dopamine modulatory mechanisms further contributing to the development of PD. Interestingly, substance P levels and immunoreactivity are decreased in nigral and striatal tissues of animals models of PD and in postmortem samples of PD patients [16Chen LW, Yung KK, Chan YS. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease Curr Drug Targets 2004; 5(2): 197-206.].

To test the hypothesis that the ACE I/D polymorphism is associated with PD, possibly through altering substance P levels, we determined ACE genotypes in PD patients and compared them to non-PD controls. The frequency of the DD genotype and the D allele was higher in the PD population. The frequency of the DD phenotype was also higher in younger patients and in patients with the akinetic-rigid type of PD. However, statistical significance was not reached in any of the comparisons made throughout our study. However, the marginally non-significant increased prevalence of DD homozygotes in the akinetic-rigid predominant PD patients may suggest that the I/D polymorphism has disease modifying effects. Mellick et al. [6Mellick GD, Buchanan DD, McCann SJ, et al. The ACE deletion polymorphism is not associated with Parkinson's disease Eur Neurol 1999; 41(2): 103-6.] were the first to investigate the possible involvement of the ACE gene in the pathogenesis of PD in a population of Caucasians. Based on evidence linking the DD ACE genotype to longevity [34Schachter F, Faure-Delanef L, Guenot F, et al. Genetic associations with human longevity at the APOE and ACE loci Nat Genet 1994; 6(1): 29-32.] they suggested that D allele may confer some long-term protective effect as a result of ACE' s action on neuropeptides and neuroendocrine function. In their study similar frequencies were reported for the D and I alleles in the PD (D 48% and I 52%) and control population (D 54% and I 46%). Furthermore, the genotype distribution was also similar in the PD and control group (the most frequent phenotype was ID in 52% of PD patients and 56% of controls). Our results are in agreement with those of Mellick et al. that also failed to provide evidence that the ACE polymorphism is related to PD. Both our studies report similar allele frequencies in the control groups confirming previous results (the reported D allele frequency in Caucasians is 50–58% [35Lin JJ, Yueh KC, Harn HJ, Chang DC, Chang CY, Yeh YH. Lack of association between deletion polymorphism of the ACE gene and ischemic vascular diseases in a Chinese population in Taiwan Zhonghua Yi Xue Za Zhi (Taipei) 1999; 62(11): 756-63., 36Sharma P. Meta-analysis of the ACE gene in ischemic stroke J Neurol Neurosurg Psychiatry 1998; 64: 227-30.].

In a different study, Lin et al. [5Lin JJ, Yueh KC, Chang DC, Lin SZ. Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease J Neurol Sci 2002; 199(1-2): 25-9.] also evaluated the possible relationship between the ACE polymorphism and PD in a Chinese population. The frequency of the homozygote DD genotype of the ACE gene was increased in the PD group (22% in the PD vs 12% in the control group), but the statistical significance was marginal (p = 0.048). The increase in the DD genotype in the PD group was also noted in our study (39% in the PD vs 32% in the control group) but significance was not reached. One could speculate that various reasons like ethnicity, (Caucasians and Chinese have different genetic backrounds), sample size and different recruitment methods used for the control population could account for this difference in significance between the two studies. In normal Chinese the D allele frequency is 35–39% [36Sharma P. Meta-analysis of the ACE gene in ischemic stroke J Neurol Neurosurg Psychiatry 1998; 64: 227-30.]. The frequency of D allele in the control subjects in the study by Lin et al. (33%) was markedly different from that in our report (57%) and Mellick’s study (54%). However, this is in accordance with the frequencies of the D allele in Caucasian and Chinese populations.

Our study has certain strengths and limitations. We acknowledge the relatively small sample size and highlight the preliminary nature of these findings. Strengths of our study include its prospective nature and the homogeneity of the sample population.

Based on the evidence presented herein, we conclude that the ACE insertion/deletion polymorphism is not associated with PD and that ACE genotypes do not correlate significantly with any of the symptoms of the disease in Caucasians, although a disease modifying effect cannot be excluded. Our data suggest that ACE genotype is unlikely to be an important determinant of susceptibility to PD.

ACKNOWLEDGEMENTS

We would like to thank the participants and their families for making these studies possible.

REFERENCES

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[2] Papapetropoulos S, Lieberman A, Gonzalez J, Mash DC. Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease? Acta Neurol Scand 2005; 111(6): 353-9.
[3] Kolsch H, Jessen F, Freymann N, et al. ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia Neurosci Lett 2005; 377(1): 37-9.
[4] Meng Y, Baldwin CT, Bowirrat A, et al. Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community Am J Hum Genet 2006; 78(5): 871-7.
[5] Lin JJ, Yueh KC, Chang DC, Lin SZ. Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease J Neurol Sci 2002; 199(1-2): 25-9.
[6] Mellick GD, Buchanan DD, McCann SJ, et al. The ACE deletion polymorphism is not associated with Parkinson's disease Eur Neurol 1999; 41(2): 103-6.
[7] Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists Pharmacol Rev 1993; 45(2): 205-51.
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[9] Reiser G, Binmoller FJ, Donie F. Mechanisms for activation and subsequent removal of cytosolic Ca2+ in bradykinin-stimulated neuronal and glial cell lines Exp Cell Res 1990; 186(1): 47-53.
[10] Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels J Clin Invest 1990; 86(4): 1343-6.
[11] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases J Neurol Neurosurg Psychiatry 1992; 55(3): 181-4.
[12] Fahn S, Elton RL. Members of the UPDRS Development Committee Unified Parkinson's Disease Rating Scale In: Fahn S, Marsden CD, Calne DB, Eds. Recent developments in Parkinson's disease. 2nd ed. Florham Park, NJ: Macmillan Health Care Information 1987; pp. 153-64.
[13] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality Neurology 1967; 17(5): 427-.
[14] Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson's disease In: Gillinghm FD, IMl , Eds. Third symposium of Parkinson's disease. Edinburgh: Livingstone 1969; pp. 152-7.
[15] Skidgel RA, Defendini R, Erdos EG. Angiotensin I converting enzyme and its role in neuropeptide metabolism In: Turner AJ, Ed. Neuropepetides and their peptidases. New York: Ellis Horwood 1987; pp. 165-82.
[16] Chen LW, Yung KK, Chan YS. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease Curr Drug Targets 2004; 5(2): 197-206.
[17] Sanberg PR, Emerich DF, Aebischer P, et al. Substance P containing polymer implants protect against striatal excitotoxicity Brain Res 1993; 628(1-2): 327-9.
[18] Barker R. Substance P and Parkinson's disease: a causal relationship? J Theor Biol 1986; 120(3): 353-62.
[19] Kalivas PW, Deutch AY, Maggio JE, Mantyh PW, Roth RH. Substance K and substance P in the ventral tegmental area Neurosci Lett 1985; 57(3): 241-6.
[20] Kelley AE, Cador M, Stinus L. Behavioral analysis of the effect of substance P injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat Psychopharmacology (Berl) 1985; 85(1): 37-46.
[21] Stoessl AJ, Szczutkowski E, Glenn B, Watson I. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions Brain Res 1991; 565(2): 254-62.
[22] Napier TC, Mitrovic I, Churchill L, Klitenick MA, Lu XY, Kalivas PW. Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P Neuroscience 1995; 69(1): 59-70.
[23] Furmidge LJ, Duggan AW, Arbuthnott GW. Substance P release from rat nucleus accumbens and striatum: an in vivo study using antibody microprobes Brain Res 1993; 610(2): 234-41.
[24] Khan S, Brooks N, Whelpton R, Michael-Titus AT. Substance P-(1-7) and substance P-(5-11) locally modulate dopamine release in rat striatum Eur J Pharmacol 1995; 282(1-3): 229-33.
[25] Glowinski J, Kemel ML, Desban M, et al. Distinct presynaptic control of dopamine release in striosomal- and matrix-enriched areas of the rat striatum by selective agonists of NK1, NK2 and NK3 tachykinin receptors Regul Pept 1993; 46(1-2): 124-8.
[26] Tremblay L, Kemel ML, Desban M, Gauchy C, Glowinski J. Distinct presynaptic control of dopamine release in striosomal- and matrix-enriched areas of the rat striatum by selective agonists of NK1, NK2, and NK3 tachykinin receptors Proc Natl Acad Sci USA 1992; 89(23): 11214-8.
[27] Kemel ML, Desban M, Glowinski J, Gauchy C. Distinct presynaptic control of dopamine release in striosomal and matrix areas of the cat caudate nucleus Proc Natl Acad Sci USA 1989; 86(22): 9006-10.
[28] Anderson JJ, Chase TN, Engber TM. Substance P increases release of acetylcholine in the dorsal striatum of freely moving rats Brain Res 1993; 623(2): 189-94.
[29] Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1) Nucleic Acids Res 1992; 20(6): 1433.
[30] Esther CR, Marino EM, Howard TE, et al. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice J Clin Invest 1997; 99(10): 2375-85.
[31] Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels Am J Hum Genet 1992; 51(1): 197-205.
[32] Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism Circulation 1995; 92(6): 1387-8.
[33] Mandel S, Grunblatt E, Riederer P, Gerlach M, Levites Y, Youdim MB. Neuroprotective strategies in Parkinson's disease : an update on progress CNS Drugs 2003; 17(10): 729-62.
[34] Schachter F, Faure-Delanef L, Guenot F, et al. Genetic associations with human longevity at the APOE and ACE loci Nat Genet 1994; 6(1): 29-32.
[35] Lin JJ, Yueh KC, Harn HJ, Chang DC, Chang CY, Yeh YH. Lack of association between deletion polymorphism of the ACE gene and ischemic vascular diseases in a Chinese population in Taiwan Zhonghua Yi Xue Za Zhi (Taipei) 1999; 62(11): 756-63.
[36] Sharma P. Meta-analysis of the ACE gene in ischemic stroke J Neurol Neurosurg Psychiatry 1998; 64: 227-30.

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Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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