Parkinson's disease is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic ...denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiologic assay. Electrically induced and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, whereas acetylcholine levels were assayed in the incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors were assessed by immunohistochemistry or western blot assay. As compared with control rats, at week 4, 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate, impaired electrically evoked neurogenic cholinergic contractions, enhanced carbachol-induced contractions, decreased basal and electrically stimulated acetylcholine release from colonic tissues, decreased ChAT immunopositivity in the neuromuscular layer, unchanged density of HuC/D immunoreactive myenteric neurons, and increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were also detected at week 8 post 6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate.
Patients with Parkinson's disease develop motor disturbances often accompanied by peripheral autonomic dysfunctions, including gastrointestinal disorders, such as dysphagia, gastric stasis and ...constipation. While the mechanisms subserving enteric autonomic dysfunctions are not clearly understood, they may involve the enteric dopaminergic and/or nitrergic systems. In the present study, we demonstrate that rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons develop a marked inhibition of propulsive activity compared to sham-operated controls, as indicated by a 60% reduction of daily fecal output at the 4th week of observation. Immunohistochemical data revealed that 6-hydroxydopamine treatment did not affect the total number of HuC/D-positive myenteric neurons in both the proximal and distal segments of ileum and colon. Conversely, in the distal ileum and proximal colon the number of nitrergic neurons was significantly reduced. These results suggest that a disturbed distal gut transit, reminiscent of constipation in the clinical setting, may occur as a consequence of a reduced propulsive motility, likely due to an impairment of a nitric oxide-mediated descending inhibition during peristalsis.
Background
Constipation is extremely common in patients with Parkinson's disease (PD) and has been described in PD animal models. In this study, we investigated whether a PD‐like degeneration of ...dopaminergic neurons of the substantia nigra can influence peristalsis in colonic segments of rats by impacting on enteric dopaminergic transmission.
Methods
Male, Sprague–Dawley rats received a unilateral injection of neurotoxin 6‐hydroxydopamine (6‐OHDA), or saline, into the medial‐forebrain‐bundle. Peristaltic activity was recorded in isolated colonic segments, in baseline conditions and following exposure to combinations of D2 receptor (DRD2) agonist sumanirole and antagonist L‐741626. Dopamine levels and DRD2 expression were assessed in the ileum and colon of animals. We also investigated the involvement of the dorsal motor nucleus of the vagus (DMV) — a potential relay station between central dopaminergic denervation and gastrointestinal (GI) dysfunction — by analyzing cytochrome c oxidase activity and FosB/DeltaFosB expression in DMV neurons.
Key Results
We observed profound alterations in the response of colonic segments of 6‐OHDA lesioned animals to DRD2 stimulation. In fact, the inhibition of colonic peristalsis elicited by sumanirole in control rats was absent in 6‐OHDA‐lesioned animals. These animals also showed reduced DRD2 expression in the colon, along with elevation of dopamine levels. No significant changes were detected within the DMV.
Conclusions & Inferences
Our results demonstrate that selective lesion of the nigrostriatal dopaminergic pathway subverts the physiological response of the colon to dopaminergic stimulation, opening new perspectives in the comprehension and treatment of GI dysfunctions associated with PD.
Rats bearing a 6‐OHDA induced lesion of the nigrostriatal tract show profound alterations in the response of colonic segments to dopaminergic D2 stimulation. In fact, the inhibition of colonic peristalsis elicited by D2 agonist sumanirole in control rats was absent in 6‐OHDA‐lesioned animals. These animals also showed reduced DRD2 expression in the colon, along with elevation of dopamine levels. Our results demonstrate that selective lesion of the nigrostriatal dopaminergic pathway subverts the physiological response of the colon to dopaminergic stimulation, opening new perspectives in the comprehension and treatment of GI dysfunctions associated with PD.
Sprague–Dawley rats received a unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum and were treated daily for 6 weeks with increasing doses of monoamine oxidase type B inhibitor ...rasagiline
R(+)-
N-propargyl-1-aminoindane or saline (controls). Both doses of rasagiline markedly increased the survival of dopaminergic neurons in the lesioned substantia nigra, compared to controls (+97% and +119%, respectively). Treatment with the lower dose of rasagiline also abolished the motor stereotypies associated with nigrostriatal lesion. Our study supports the neuroprotective potential of chronic rasagiline administration in an experimental model of Parkinson's disease (PD).
Background
The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for ...CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission.
Aim
The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia.
Results
MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30–60 minutes before) NTG.
Conclusion
These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.
We have previously shown that human mesenchymal stem cells (hMSCs) can reduce toxin-induced neurodegeneration in a well characterized rodent model of Parkinson's disease. However, the precise ...mechanisms, optimal cell concentration required for neuroprotection, and detailed cell tracking need to be defined. We exploited a near-infrared imaging platform to perform noninvasive tracing following transplantation of tagged hMSCs in live parkinsonian rats.
hMSCs were labeled both with a membrane intercalating dye, emitting in the near- infrared 815 nm spectrum, and the nuclear counterstain, Hoechst 33258. Effects of near-infrared dye on cell metabolism and proliferation were extensively evaluated in vitro. Tagged hMSCs were then administered to parkinsonian rats bearing a 6-hydroxydopamine-induced lesion of the nigrostriatal pathway, via two alternative routes, ie, intrastriatal or intranasal, and the cells were tracked in vivo and ex vivo using near-infrared technology.
In vitro, NIR815 staining was stable in long-term hMSC cultures and did not interfere with cell metabolism or proliferation. A significant near-infrared signal was detectable in vivo, confined around the injection site for up to 14 days after intrastriatal transplantation. Conversely, following intranasal delivery, a strong near-infrared signal was immediately visible, but rapidly faded and was completely lost within 1 hour. After sacrifice, imaging data were confirmed by presence/absence of the Hoechst signal ex vivo in coronal brain sections. Semiquantitative analysis and precise localization of transplanted hMSCs were further performed ex vivo using near-infrared imaging.
Near-infrared technology allowed longitudinal detection of fluorescent-tagged cells in living animals giving immediate information on how different delivery routes affect cell distribution in the brain. Near-infrared imaging represents a valuable tool to evaluate multiple outcomes of transplanted cells, including their survival, localization, and migration over time within the host brain. This procedure considerably reduces the number of animal experiments needed, as well as interindividual variability, and may favor the development of efficient therapeutic strategies promptly applicable to patients.
Abstract Alteration of key regulatory kinases may cause aberrant protein phosphorylation and aggregation in Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we investigated ...expression and phosphorylation status of glycogen synthase kinase 3 (GSK-3), protein kinase B (Akt) and tau protein in peripheral blood lymphocytes of 20 AD, 25 PD patients and 20 healthy controls. GSK-3 was increased in AD and PD patients. In these latter, GSK-3 levels were positively correlated with daily l -Dopa intake. Phosphorylated Akt expression was augmented in both groups; total Akt levels were increased only in AD patients and were positively correlated with disease duration and severity. Total and phosphorylated tau were increased only in AD, with phospho-tau levels being positively correlated with levels of total tau, Akt, and disease duration. No correlations between protein levels and clinical variables were found in PD patients. Investigation of peripheral changes in the expression of specific kinases may, therefore, lead to the development of innovative biomarkers of neurodegeneration, particularly for AD.
Abstract The loss of nigrostriatal dopaminergic neurons that characterizes Parkinson's disease (PD) causes complex functional alterations in the basal ganglia circuit. Increased glutamatergic ...activity at crucial points of the circuit may be central to these alterations, thereby contributing to the onset of PD motor symptoms. Signs of neuroinflammation accompanying the neuronal loss have also been observed; also in this case, glutamate-mediated mechanisms may be involved. Glutamate may therefore intervene at multiple levels in PD pathophysiology, possibly through the modulation of metabotropic receptors. To address this issue, we evaluated the effects of systemic treatment with MPEP (2-methyl-6-(phenylethynyl)-pyridine), an antagonist of metabotropic receptor mGluR5, in a rodent model of progressive nigrostriatal degeneration based on the intrastriatal injection of 6-hydroxydopamine (6-OHDA). Following 6-OHDA injection, Sprague-Dawley rats underwent a 4-week, daily treatment with MPEP (1.5 mg/kg, i.p.). To investigate whether the effects varied with the progression of the lesion, subgroups of lesioned animals started the treatment at different time-points: (1) immediately, (2) 1 week, or (3) 4 weeks after the neurotoxin injection. Akinesia, dopaminergic nigrostriatal damage and neuroinflammatory response (microglial and astroglial activation) were investigated. MPEP prompted immediate amelioration of 6-OHDA-induced akinesia, as measured by the Adjusting step test, in all subgroups, regardless of the degree of nigrostriatal damage. Conversely, MPEP did not modify neuronal survival or neuroinflammatory response in the nigrostriatal pathway. In conclusion, chronic treatment with MPEP exerted a pure symptomatic effect, further supporting that mGluR5 modulation may be a viable strategy to counteract the basal ganglia functional modifications underlying PD motor symptoms.
Defects of the ubiquitin-proteasome (UP) system, a multicatalytic complex degrading polyubiquitinated proteins, may intervene in the pathogenesis of neurodegenerative disorders characterized by ...intracellular formation of protein aggregates such as Parkinson disease (PD) and Alzheimer disease (AD) by inducing proapoptotic conditions.
The authors measured the activity of proteolytic UP core, proteasome 20S, and of proapoptotic caspase-3 and -9 in peripheral blood lymphocytes (PBLs) of PD and AD patients to establish whether changes in these systems are detectable peripherally.
Proteasome 20S activity was reduced in PBLs of treated PD patients vs healthy controls (mean +/- SEM: 1.0 +/- 0.1 vs 2.3 +/- 0.2 nmol 7-amino-4-methylcoumarin (AMC)/10(6) cells, p < 0.001), whereas marked increases in caspase-3 activity (1370 +/- 153 vs 586 +/- 104 pmol AMC/10(6) cells, p < 0.001) and caspase-9 activity (873 +/- 86 vs 304 +/- 27 U/10(6) cells, p < 0.001) were found. Increased caspase-9 activity was also detected in PBLs of untreated PD patients (900 +/- 193 U/10(6) cells). PD duration and severity (Unified Parkinson's Disease Rating Scale score) were inversely correlated with proteasome 20S activity and directly correlated with caspase-3 activity. An inverse correlation was also observed in PD patients between caspase-3 activity and proteasome 20S activity. No significant changes in proteasome 20S or caspase activity or correlations between biochemical and clinical variables were found in patients with AD.
A decrease in proteasome activity, possibly related to caspase activation, is detectable in peripheral blood lymphocytes of patients with Parkinson disease but not patients with Alzheimer disease, suggesting that these variables may be considered for the development of peripheral biomarkers of Parkinson disease.
Objectives – While clinical hypothyroidism is associated with frank neuropsychological and affective alterations and is considered one of the causes of reversible dementia, the occurrence of these ...alterations and their treatment in mild hypothyroidism (MH) remains a controversial issue. Our aim was therefore to evaluate cognitive and psychological functions in a selected population of recently‐diagnosed MH patients with minor subjective symptoms.
Materials and methods – Thirty‐six MH women (mean age 51.9 ± 13.5 years) were observed after a careful assessment had excluded subjects with neurological, psychiatric and/or somatic disorders, or confounding conditions. The subjects were evaluated for thyroid function and tested with an extensive battery of neuropsychological tests and psychological rating scales, in basal conditions and after 6 months of l‐thyroxine treatment.
Results – Baseline neuropsychological performance was within the normal range, while an age‐dependent reduction was found in attentive function. After l‐thyroxine treatment, an increase in serum fT4 was detected in parallel with thyroid stimulating hormone (TSH) reduction. Verbal fluency and depression scores showed a slight improvement. A positive correlation was found between TSH reduction and improved mood scores.
Conclusion – From the analysis of the results, treatment of asymptomatic MH would seem advisable in order to re‐set hormonal levels and, particularly in older subjects, to protect the brain against the potential risk of cognitive and affective dysfunctions.
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