Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer’s disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.

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Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.

BACKGROUNDInflammatory bowel diseases (IBD) have been associated with a low quality of life (QoL) and a negative impact on work productivity compared to the general population. Information about disease control, patient-reported outcomes (PROs), treatment patterns and use of healthcare resources is relevant to optimizing IBD management.AIMTo describe QoL and work productivity and activity impairment (WPAI), treatment patterns and use of healthcare resources among IBD patients in Brazil.METHODSA multicenter cross-sectional study included adult outpatients who were previously diagnosed with moderate to severe Crohn’s disease (CD) or ulcerative colitis (UC). At enrolment, active CD and UC were defined as having a Harvey Bradshaw Index ≥ 8 or a CD Activity Index ≥ 220 or calprotectin > 200 µg/g or previous colonoscopy results suggestive of inadequate control (per investigator criteria) and a 9-point partial Mayo score ≥ 5, respectively. The PRO assessment included the QoL questionnaires SF-36 and EQ-5D-5L, the Inflammatory Bowel Disease Questionnaire (IBDQ), and the WPAI questionnaire. Information about healthcare resources and treatment during the previous 3 years was collected from medical records. Chi-square, Fisher’s exact and Student’s t-/Mann-Whitney U tests were used to compare PROs, treatment patterns and the use of healthcare resources by disease activity (α = 0.05).RESULTSOf the 407 patients in this study (CD/UC: 64.9%/35.1%, mean age 42.9/45.9 years, 54.2%/56.6% female, 38.3%/37.1% employed), 44.7%/25.2% presented moderate-to-severe CD/UC activity, respectively, at baseline. Expressed in median values for CD/UC, respectively, the SF-36 physical component was 46.6/44.7 and the mental component was 45.2/44.2, the EQ-visual analog scale score was 80.0/70.0, and the IBDQ overall score was 164.0/165.0. Moderate to severe activity, female gender, being unemployed, a lower educational level and lower income were associated with lower QoL (P < 0.05). Median work productivity impairment was 20% and 5% for CD and UC patients, respectively, and activity impairment was 30%, the latter being higher among patients with moderate to severe disease activity compared to patients with mild or no disease activity (75.0% vs 10.0%, P < 0.001). For CD/UC patients, respectively, 25.4%/2.8% had at least one surgery, 38.3%/19.6% were hospitalized, and 70.7%/77.6% changed IBD treatment at least once during the last 3 years. The most common treatments at baseline were biologics (75.3%) and immunosuppressants (70.9%) for CD patients and 5-ASA compounds (77.5%) for UC patients.CONCLUSIONModerate to severe IBD activity, especially among CD patients, is associated with a substantial impact on QoL, work productivity impairment and an increased number of IBD surgeries and hospitalizations in Brazil.

BackgroundThe metabotropic glutamate receptor 5 (mGluR5) is involved in various brain functions, including memory, cognition and motor behavior. Regarding locomotor activity, we and others have demonstrated that pharmacological antagonism of mGluR5 promotes hyperkinesia in mice. Moreover, increased locomotor activity can also be observed in mice following the genetic deletion of mGluR5. However, it is still unclear which specific brain substrates contribute to mGluR5-mediated regulation of motor function.ResultsThus, to better understand the role of mGluR5 in motor control and to determine which neural substrates are involved in this regulation we performed stereotactic microinfusions of the mGluR5 antagonist, MPEP, into specific brain regions and submitted mice to the open field and rotarod apparatus. Our findings indicate that mGluR5 blockage elicits distinct outcomes in terms of locomotor activity and motor coordination depending on the brain region injected with mGluR5 antagonist. MPEP injection into either the dorsal striatum or dorsal hippocampus resulted in increased locomotor activity, whereas MPEP injection into either the ventral striatum or motor cortex resulted in hypokinesia. Moreover, MPEP injected into the olfactory bulb increased the distance mice traveled in the center of the open field arena. With respect to motor coordination on the rotarod, injection of MPEP into the motor cortex and olfactory bulb elicited decreased latency to fall.ConclusionsTaken together, our data suggest that not only primarily motor neural substrates, but also limbic and sensory structures are involved in mGluR5-mediated motor behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0113-2) contains supplementary material, which is available to authorized users.

Although the data published so far strongly indicate that mGluR5 plays a major role in HD-associated neurodegeneration, htt aggregation and motor symptoms, it is not clear whether mGluR5 stimulation can diminish or intensify neuronal cell loss and HD progression. Thus, future experiments will be necessary to further investigate the outcome of drugs acting on mGluR5 for the treatment of neurodegenerative diseases.

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