Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation

Singaram, Chandar; Gaumnitz, Eric A.; Torbey, Camille F.; Ashraf, Waseem; Quigley, Eamonn Martin; Sengupta, A.; Pfeiffer, Ronald F.

doi:10.1016/s0140-6736(95)92707-7

Cited by 321 publications

(228 citation statements)

References 11 publications

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“…Loss of enteric dopamine neurons has been reported in PD, but the typical gastrointestinal symptom profile exhibited by PD patients includes delayed gastric emptying and constipation, which MPTP-treated mice do not develop (Pfeiffer, 2003, Pfeiffer and Quigley, 1999, Singaram, et al, 1995. In fact, dopaminergic damage transiently causes colonic hypermotility in mice, which is similar to results previously reported in D2 dopamine receptor knockout mice (Li, et al, 2006).…”

Section: Discussionsupporting

confidence: 80%

“…With that background, detailed neurochemical coding of ENS damage from PD patients should provide a foundation for rationally designed GI therapies based on the specific neuropathological pattern of ENS damage in PD. Furthermore, given the effects noted in the lower GI tract, colorectal biopsy of PD patients may provide the means to routinely neuropathologically diagnose and monitor PD in living patients (Singaram, et al, 1995). Finally, animal models of PD that exhibit ENS pathology may provide a tool to confirm or refute hypotheses related to pathogenesis and selective vulnerability in parkinsonism (Braak, et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Lewy bodies have been described in both the myenteric and submucosal plexuses of the ENS (Braak, et al, 2006, Kupsky, et al, 1987, Singaram, et al, 1995, Wakabayashi, et al, 1990, Wakabayashi, et al, 1988, Wakabayashi, et al, 1989, and other research has found lower levels of enteric dopaminergic neurons in ENS of PD patients (Singaram, et al, 1995). Central areas associated with gastrointestinal motility have also been implicated.…”

Section: Introductionmentioning

confidence: 98%

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Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

205

196

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Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

205

196

View full text Add to dashboard Cite

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“…Central as well as peripheral DA has been reported to modulate GI functions in mammals and protect against ulcer formation induced by chemicals or stress (31)(32)(33)(34). Notably, loss of DA in Parkinson's disease is accompanied by a high incidence of duodenal ulcers (35) and by impaired GI motility (36). DA inhibits gastric acid secretion, enhancing submucosal blood flow and regulating GI motility.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Kobayashi

Iaccarino

Saiardi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative͞synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1͞D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r ؊/؊ ;D2r ؉/؊ ) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r͞D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the singlegene ablation studies.knockout mice ͉ motor function ͉ feeding behavior ͉ gastrointestinal system T he diverse physiological functions of dopamine (DA) are mediated by five distinct receptors, which by structural and pharmacological means have been grouped into two families: the D1-like and D2-like receptors. The D1-like family comprises the D1 and D5 receptors, whereas D2, D3, and D4 receptors form the D2-like family. Pharmacological studies have not allowed a full understanding of the specific role of each DA receptor in vivo because of the lack of ligands with absolute receptor specificity. Knockout mice for each DA receptor have now been reported (1-9), substantially increasing our knowledge of the dopaminergic system (10, 11).Among DA receptors the most widely and abundantly expressed in the central nervous system are the D1 and D2 receptors, whereas D3, D4, and D5 have lower abundance and a very restricted localization. Mutation of the D1 gene (D1r) in mice resulted in growth retardation, failure to respond to the motor stimulant effects of addictive drugs, and poor learning performance (2,3,(12)(13)(14). Moderate growth retardation was also reported in mice lacking D2 receptors (D2r Ϫ/Ϫ ), which in addition are hypoactive, fail to experience the rewarding properties of morphine, and lose DA autoreceptor function (4, 15, 16).Importantly, neuroanatomical as well as pharmacological studies have pro...

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“…This nucleus seems to be affected in PD (139) and within the enteric nervous system in the gut abnormalities, such as loss of dopaminergic neurons and Lewy bodies, have also been shown (140,141). As mentioned earlier, a hypothesis is that PD pathology starts in the gut and spreads towards the central nervous system (CNS) (136).…”

Section: Gastric Emptyingmentioning

confidence: 88%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation

Cited by 321 publications

References 11 publications

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

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