[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 50.16.52.237. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure.
Inverse correlation between brain dopamine loss in Parkinson disease (PD) and tissue noradrenaline levels. A, Noradrenaline levels in subdivisions of the nucleus accumbens (NACS) of control subjects and the percentage dopamine loss in the corresponding accumbens subdivisions of patients with PD. Data are mean ± SEM. *P<.001, †P=.007, and ‡P=.07, PD vs control in dopamine levels (2-tailed t tests with Bonferroni adjustment). c Indicates caudal; i, intermediate; and r, rostral. Note the high concentration of noradrenaline and the low extent of dopamine loss in the medial portion of the caudal accumbens (solid bar) in PD. B, Correlation (Pearson product moment correlation) between dopamine loss in PD and levels of noradrenaline in control subjects in the 20 brain areas as given in Table 2. The solid circles indicate subdivisions of the striatum (caudate, putamen, and NACS). Noradrenaline levels in the NACS of the control subjects have been published and are reproduced with permission from the International Society for Neurochemistry.

Inverse correlation between brain dopamine loss in Parkinson disease (PD) and tissue noradrenaline levels. A, Noradrenaline levels in subdivisions of the nucleus accumbens (NACS) of control subjects and the percentage dopamine loss in the corresponding accumbens subdivisions of patients with PD. Data are mean ± SEM. *P<.001, †P=.007, and ‡P=.07, PD vs control in dopamine levels (2-tailed t tests with Bonferroni adjustment). c Indicates caudal; i, intermediate; and r, rostral. Note the high concentration of noradrenaline and the low extent of dopamine loss in the medial portion of the caudal accumbens (solid bar) in PD. B, Correlation (Pearson product moment correlation) between dopamine loss in PD and levels of noradrenaline in control subjects in the 20 brain areas as given in Table 2. The solid circles indicate subdivisions of the striatum (caudate, putamen, and NACS). Noradrenaline levels in the NACS of the control subjects have been published11 and are reproduced with permission from the International Society for Neurochemistry.

Table 1.  
Patient Information*
Patient Information*
Table 2.  
Levels of Dopamine and Noradrenaline in Brains of Patients With Parkinson Disease (PD)*
Levels of Dopamine and Noradrenaline in Brains of Patients With Parkinson Disease (PD)*
1.
Hornykiewicz  O Biochemical aspects of Parkinson's disease. Neurology 1998;51(suppl 2)S2- S9
PubMedArticle
2.
Zarow  CLyness  SAMortimer  JAChui  HC Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 2003;60337- 341
PubMedArticle
3.
Rye  DDeLong  MR Time to focus on the locus [editorial]. Arch Neurol 2003;60320
PubMedArticle
4.
Marien  MRColpaert  FCRosenquist  AC Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Brain Res Rev 2004;4538- 78
PubMedArticle
5.
McGeer  PLItagaki  SBoyes  BEMcGeer  EG Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988;381285- 1291
PubMedArticle
6.
Imamura  KHishikawa  NSawada  MNagatsu  TYoshida  MHashizume  Y Distribution of major histocompatibility complex class II–positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol (Berl) 2003;106518- 526
PubMedArticle
7.
Ouchi  YYoshikawa  ESekine  Y  et al.  Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 2005;57168- 175
PubMedArticle
8.
Gerhard  APavese  NHotton  G  et al.  In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 2006;21404- 412
PubMedArticle
9.
Heneka  MTGavrilyuk  VLandreth  GEO’Banion  MKWeinberg  GFeinstein  DL Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression. J Neurochem 2003;85387- 398
PubMedArticle
10.
Heneka  MTRamanathan  MJacobs  AH  et al.  Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 2006;261343- 1354
PubMedArticle
11.
Tong  JHornykiewicz  OKish  SJ Identification of a noradrenaline-rich subdivision of the human nucleus accumbens. J Neurochem 2006;96349- 354
PubMedArticle
12.
Wilson  JMNobrega  JNCarroll  ME  et al.  Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. J Neurosci 1994;142966- 2979
PubMed
13.
Kish  SJShannak  KHornykiewicz  O Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease: pathophysiologic and clinical implications. N Engl J Med 1988;318876- 880
PubMedArticle
14.
Shannak  KRajput  ARozdilsky  BKish  SGilbert  JHornykiewicz  O Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects. Brain Res 1994;63933- 41
PubMedArticle
15.
Mavridis  MDegryse  ADLategan  AJMarien  MRColpaert  FC Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson's disease. Neuroscience 1991;41507- 523
PubMedArticle
16.
Marien  MBriley  MColpaert  F Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice. Eur J Pharmacol 1993;236487- 489
PubMedArticle
17.
Fornai  FAlessandri  MGTorracca  MTBassi  LCorsini  GU Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions. J Pharmacol Exp Ther 1997;283100- 107
PubMed
18.
Srinivasan  JSchmidt  WJ Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine–induced rat model of Parkinson's disease. Behav Brain Res 2004;151191- 199
PubMedArticle
19.
Srinivasan  JSchmidt  WJ Treatment with α2-adrenoceptor antagonist, 2-methoxy idazoxan, protects 6-hydroxydopamine–induced Parkinsonian symptoms in rats: neurochemical and behavioral evidence. Behav Brain Res 2004;154353- 363
PubMedArticle
20.
Rommelfanger  KSWeinshenker  DMiller  GW Reduced MPTP toxicity in noradrenaline transporter knockout mice. J Neurochem 2004;911116- 1124
PubMedArticle
21.
Fawcett  JPBamji  SXCausing  CG  et al.  Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS. J Neurosci 1998;182808- 2821
PubMed
22.
Gao  HMLiu  BZhang  WHong  JS Novel anti-inflammatory therapy for Parkinson's disease. Trends Pharmacol Sci 2003;24395- 401
PubMedArticle
23.
Lemke  MR Effect of reboxetine on depression in Parkinson's disease patients. J Clin Psychiatry 2002;63300- 304
PubMedArticle
24.
Pintor  LBailles  EValldeoriola  FTolosa  EMarti  MJde Pablo  J Response to 4-month treatment with reboxetine in Parkinson's disease patients with a major depressive episode. Gen Hosp Psychiatry 2006;2859- 64
PubMedArticle
Original Contribution
December 2006

Inverse Relationship Between Brain Noradrenaline Level and Dopamine Loss in Parkinson DiseaseA Possible Neuroprotective Role for Noradrenaline

Author Affiliations

Author Affiliations: Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario (Drs Tong and Kish); and Center for Brain Research, Medical University of Vienna, Vienna, Austria (Dr Hornykiewicz).

Arch Neurol. 2006;63(12):1724-1728. doi:10.1001/archneur.63.12.1724
Abstract

Background  Experimental findings using animal models of Parkinson disease (PD) suggest that noradrenaline might protect dopamine neurons from damage.

Objective  To assess whether human brain regions having high levels of noradrenaline are less susceptible to dopamine loss in PD.

Design  Case-control study.

Setting  Postmortem investigation.

Participants  Autopsied brains of patients with PD and of healthy control subjects.

Main Outcomes Measures  We compared the extent of dopamine loss in different regions relative to levels of noradrenaline found in healthy brain, with special attention devoted to the dopamine-rich nucleus accumbens, which has noradrenaline-rich and noradrenaline-poor subdivisions.

Results  Among 20 brain areas, dopamine loss in PD was negatively correlated with healthy noradrenaline levels (r = 0.83), with regions rich in noradrenaline (eg, the noradrenaline-rich portion of the nucleus accumbens) spared from dopamine loss. However, within the striatum, noradrenaline levels in the caudate and putamen were similar, despite dopamine's being more markedly reduced in the putamen.

Conclusions  Our postmortem data are consistent with animal findings suggesting that noradrenaline might affect dopamine neuron loss in PD and that a noradrenergic approach (although not aimed at the as yet unknown primary cause of PD) could be neuroprotective. This possibility should also be considered when noradrenergic therapy is provided for symptomatic purposes in PD.

Idiopathic Parkinson disease (PD) is characterized by heterogeneous degeneration of brain dopamine neurons.1 The cause of PD is unknown, and the reason why dopamine neurons in some brain areas are much more vulnerable to damage than those in others is unknown.

Neuropathological observations in PD of the loss of noradrenergic neurons originating in the locus coeruleus area2 suggest that noradrenaline therapy might be helpful in symptomatic treatment of some aspects of PD.3 Moreover, animal findings suggest that the loss of brain noradrenergic neurons in PD might exacerbate dopamine neuron damage and that noradrenaline could actually be neuroprotective.4 The possible involvement of noradrenaline is especially interesting given findings of brain microglial activation in PD58 and the emerging role for noradrenaline as an endogenous anti-inflammatory agent.9,10

If the experimental animal data are relevant to the human, one might expect that brain regions having high levels of noradrenaline could be more protected against dopamine loss in PD. To address this possibility, we compared the extent of dopamine loss in different regions in autopsied brains of patients with PD with levels of noradrenaline found in healthy brain. Of 20 areas examined, an area of focus was the dopamine-rich nucleus accumbens (NACS), a striatal subdivision that contains a noradrenaline-poor rostral portion and a caudomedial subdivision that is strikingly enriched in noradrenaline.11

METHODS

Autopsied brains were obtained (February 1982 to December 1990) from patients with PD (n = 10) and from healthy control subjects (n = 11). The control subjects and the patients with PD did not differ significantly in their mean (SD) ages (70.6 [9.9] and 75.8 [7.4] years, respectively; P = .20 or in their mean postmortem intervals before autopsy (9.3 [4.2] and 12.8 [5.9] hours, respectively; P = .14) (2-tailed t tests). Half of the brain was used for neuropathological examination, whereas the other half was frozen for neurochemical analyses. Clinical, drug history, and brain neuropathological findings for the patients with PD are summarized in Table 1. All patients had received the clinical diagnosis of PD except for patient 8, who had been observed only briefly by a neurologist a few days before death and was considered at that time to have a neurological illness characterized by tremor. Postmortem brain neurochemical analyses of this patient showed the pattern of striatal dopamine loss that is characteristic of PD, and brain neuropathological analyses of this patient and all other patients with the clinical diagnosis of PD disclosed the characteristic histopathological signs of substantia nigra cell loss and the presence of Lewy bodies. All patients except for patient 8 had received dopamine substitution medication. No detailed information on the neuropsychological or mental function of the patients was available. Control subjects had died without evidence of neurological or psychiatric disease and showed no brain abnormality on neuropathological examination. The causes of death for the control subjects were myocardial infarction (n = 3), cardiac failure (n = 2), cancer (n = 2), pulmonary embolism (n = 2), diffuse interstitial pulmonary disease (n = 1), and unknown (n = 1).

Dissection of the brains and subdivisions of the striatum, including the NACS, followed procedures that have been published elsewhere.11 Levels of dopamine and noradrenaline were measured by high-performance liquid chromatography–electrochemical detection.12 The primary outcome measure was correlation (Pearson product-moment correlation) among the brain areas examined between percentage dopamine loss in PD vs noradrenaline levels in healthy brain. Two-tailed t tests with Bonferroni correction for multiple comparisons were performed to examine differences between the control and PD groups.

Some neurochemical data have been previously published. These include caudate and putamen dopamine levels in 10 control subjects and in 8 patients with PD13; hypothalamus dopamine and noradrenaline levels in 8 control subjects and in 9 patients with PD14; and NACS dopamine and noradrenaline levels in 11 control subjects.11 No significant correlation was observed between age or postmortem interval of the subjects and tissue levels of the monoamines in the control or PD group.

RESULTS
DOPAMINE AND NORADRENALINE LOSS

Table 2 gives the control and patient levels of dopamine and noradrenaline in 1 cerebral and 19 subcortical cortical brain areas. Analysis in the cerebral cortex was limited to the cortical region, Brodmann area 25 (parolfactory cortex), which in the human contains a quantifiable amount of dopamine.

As expected, dopamine was decreased in all examined brain regions, but the magnitude of the reduction in the different brain areas was variable. Of the regions examined, the caudal portion of the putamen was the most affected (−97%) in PD, and the preoptic area of the hypothalamus was the least affected (−9%) (Table 2). Concentrations of noradrenaline were generally more modestly decreased (≤57% maximum reduction). No significant correlation (r = −0.17, P>.05) was observed between the extent of dopamine and noradrenaline loss in the 20 examined brain regions.

DOPAMINE LOSS VS NORADRENALINE CONCENTRATION

In the PD group, brain areas that in healthy subjects have high (>1 ng/mg) noradrenaline concentrations (the caudomedial NACS and rostral portions of the hypothalamus) showed less severe dopamine loss (−9% to −54%) compared with brain areas with low levels (<0.4 ng/mg) of the neurotransmitter (−61% to −97%) (Table 2). This is best exemplified by the NACS and the striatal nuclei. In the NACS, the noradrenaline-rich caudomedial portion was spared (relative to the other NACS subdivisions) from severe dopamine depletion (Figure, A), and in the noradrenaline-poor striatum, the dopamine loss was severe in the caudate and in the putamen. A correlational analysis using values from the 20 examined brain areas confirmed that the extent of the mean dopamine loss in the different brain regions was significantly inversely correlated with the levels of noradrenaline in healthy control subjects (r = 0.83, P<.001; Figure, B) and in subjects with PD (r = 0.82, P<.001). However, within the striatum (caudate and putamen), noradrenaline concentrations were low and were similar in the subdivisions that are most (caudal putamen, −97% dopamine loss) and least (caudal caudate, −61% dopamine loss) affected in PD (Table 2).

COMMENT

Notwithstanding the many uncertainties inherent in human postmortem brain studies (eg, possible medication effects), we found that regions rich in noradrenaline had smaller dopamine losses than those in noradrenaline-poor areas in PD. This is best illustrated in the dopamine-rich NACS, which has a noradrenaline-poor rostral portion and a caudal subdivision that is strikingly rich in noradrenaline11 and was particularly spared from dopamine loss in PD. This notion receives further support from the observation that dopamine loss is marked in the striatum (caudate and putamen), which contains low levels of noradrenaline. However, it is unlikely that a lack of noradrenaline could be the primary factor responsible for the dopamine neuron death. This is shown by our additional finding that levels of noradrenaline within the different subdivisions of the caudate and putamen were similar, although dopamine was much more markedly decreased in the subdivided putamen. This points to the subregionally selective effect of the still unknown primary factor (or factors) responsible for the nigrostriatal neurodegenerative process in PD.

In studies using animal models of PD caused by dopaminergic neurotoxins (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), striatal dopamine loss is more severe following lesions of the locus coeruleus noradrenergic pathway.1518 Conversely, pharmacological enhancement of noradrenergic activity by an α2-adrenergic antagonist,19 by a noradrenaline transporter inhibitor,20 or by genetic deletion of the noradrenaline transporter20 was neuroprotective. This suggests the possibility that noradrenaline might have a neuroprotective role in PD.4

The mechanism of neuroprotective action of noradrenaline in experimental studies is still debated4 but could involve the neurotrophic function of the noradrenergic brain innervation21 or, especially, the amine anti-inflammatory potential.9,10 The loss of dopamine neurons in PD is accompanied by the appearance of activated microglial cells in brain58 that would be expected to have the capacity to produce cytokines (eg, tumor necrosis factor α and interleukin 1β) and other proinflammatory molecules, thereby aggravating neuronal cell death.22 In this context, experimental studies9,10 have revealed that noradrenaline can inhibit several aspects of the microglial reaction (including the expression of tumor necrosis factor α and interleukin 1β) and thus has the potential of an endogenous anti-inflammatory agent in the brain. Future studies should establish whether the regional extent of microglial activation in PD is inversely related to the brain regional noradrenergic innervation.

CONCLUSIONS

Our postmortem brain findings (although only correlational) provide support to the notion (based on animal data) that clinical therapeutic approaches designed to enhance brain noradrenergic activity (eg, by α2-adrenergic antagonists and noradrenaline transporter inhibitors) should be considered as possible neuroprotective strategies in PD. This potential neuroprotective action of noradrenaline should also be kept in mind when treating patients having PD with noradrenergic compounds (eg, noradrenaline transporter inhibitors for depression23,24) for symptomatic purposes.

Back to top
Article Information

Correspondence: Junchao Tong, PhD, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada M5T 1R8 (junchao_tong@camh.net).

Accepted for Publication: June 16, 2006.

Author Contributions:Study concept and design: Kish and Hornykiewicz. Acquisition of data: Tong, Kish, and Hornykiewicz. Analysis and interpretation of data: Tong, Kish, and Hornykiewicz. Drafting of the manuscript: Tong, Kish, and Hornykiewicz. Critical revision of the manuscript for important intellectual content: Tong, Kish, and Hornykiewicz. Statistical analysis: Tong. Obtained funding: Kish. Administrative, technical, and material support: Kish and Hornykiewicz. Study supervision: Kish.

Financial Disclosure: None reported.

Funding/Support: The study was supported by grant DA07182 from the National Institute of Drug Abuse (Dr Kish).

References
1.
Hornykiewicz  O Biochemical aspects of Parkinson's disease. Neurology 1998;51(suppl 2)S2- S9
PubMedArticle
2.
Zarow  CLyness  SAMortimer  JAChui  HC Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 2003;60337- 341
PubMedArticle
3.
Rye  DDeLong  MR Time to focus on the locus [editorial]. Arch Neurol 2003;60320
PubMedArticle
4.
Marien  MRColpaert  FCRosenquist  AC Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Brain Res Rev 2004;4538- 78
PubMedArticle
5.
McGeer  PLItagaki  SBoyes  BEMcGeer  EG Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988;381285- 1291
PubMedArticle
6.
Imamura  KHishikawa  NSawada  MNagatsu  TYoshida  MHashizume  Y Distribution of major histocompatibility complex class II–positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol (Berl) 2003;106518- 526
PubMedArticle
7.
Ouchi  YYoshikawa  ESekine  Y  et al.  Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 2005;57168- 175
PubMedArticle
8.
Gerhard  APavese  NHotton  G  et al.  In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 2006;21404- 412
PubMedArticle
9.
Heneka  MTGavrilyuk  VLandreth  GEO’Banion  MKWeinberg  GFeinstein  DL Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression. J Neurochem 2003;85387- 398
PubMedArticle
10.
Heneka  MTRamanathan  MJacobs  AH  et al.  Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 2006;261343- 1354
PubMedArticle
11.
Tong  JHornykiewicz  OKish  SJ Identification of a noradrenaline-rich subdivision of the human nucleus accumbens. J Neurochem 2006;96349- 354
PubMedArticle
12.
Wilson  JMNobrega  JNCarroll  ME  et al.  Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. J Neurosci 1994;142966- 2979
PubMed
13.
Kish  SJShannak  KHornykiewicz  O Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease: pathophysiologic and clinical implications. N Engl J Med 1988;318876- 880
PubMedArticle
14.
Shannak  KRajput  ARozdilsky  BKish  SGilbert  JHornykiewicz  O Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects. Brain Res 1994;63933- 41
PubMedArticle
15.
Mavridis  MDegryse  ADLategan  AJMarien  MRColpaert  FC Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson's disease. Neuroscience 1991;41507- 523
PubMedArticle
16.
Marien  MBriley  MColpaert  F Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice. Eur J Pharmacol 1993;236487- 489
PubMedArticle
17.
Fornai  FAlessandri  MGTorracca  MTBassi  LCorsini  GU Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions. J Pharmacol Exp Ther 1997;283100- 107
PubMed
18.
Srinivasan  JSchmidt  WJ Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine–induced rat model of Parkinson's disease. Behav Brain Res 2004;151191- 199
PubMedArticle
19.
Srinivasan  JSchmidt  WJ Treatment with α2-adrenoceptor antagonist, 2-methoxy idazoxan, protects 6-hydroxydopamine–induced Parkinsonian symptoms in rats: neurochemical and behavioral evidence. Behav Brain Res 2004;154353- 363
PubMedArticle
20.
Rommelfanger  KSWeinshenker  DMiller  GW Reduced MPTP toxicity in noradrenaline transporter knockout mice. J Neurochem 2004;911116- 1124
PubMedArticle
21.
Fawcett  JPBamji  SXCausing  CG  et al.  Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS. J Neurosci 1998;182808- 2821
PubMed
22.
Gao  HMLiu  BZhang  WHong  JS Novel anti-inflammatory therapy for Parkinson's disease. Trends Pharmacol Sci 2003;24395- 401
PubMedArticle
23.
Lemke  MR Effect of reboxetine on depression in Parkinson's disease patients. J Clin Psychiatry 2002;63300- 304
PubMedArticle
24.
Pintor  LBailles  EValldeoriola  FTolosa  EMarti  MJde Pablo  J Response to 4-month treatment with reboxetine in Parkinson's disease patients with a major depressive episode. Gen Hosp Psychiatry 2006;2859- 64
PubMedArticle
×