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Aims Cyclophosphamide-induced cystitis alterations have been reported to occur both at efferent and afferent level in the micturition reflex arc. In particular, the stretching of the bladder wall causing urothelial release of ATP has been proposed as one of the pivotal mechanisms causing these alterations. To evaluate functional changes at efferent and afferent levels of the micturition reflex following cyclophosphamide treatment we have applied a novel in situ half bladder rat model. Methods Male Sprague-Dawley rats were treated with either saline or cyclophosphamide (100 mg/kg), and stretch-, electric-, methacholine-, and ATP-induced responses were thereafter measured at 60-72 hr postinjection under pentobarbitone anesthesia. In the novel in situ half bladder model, the urinary bladder was prepared via a midline incision, where the two halves were separated all the way to the urethra as previously described. Results Following bladder stretch of 30-80 mN, of the half that was not used for tension measurement, the cyclophosphamide-treated animals evoked significant two- to threefold larger contractile responses as compared to saline-treated control animals. A sensitization of the afferent arm was shown in cyclophosphamide-treated animals, since afferent stimulation evoked similar responses as in control animals despite that the efferent pelvic nerve stimulation displayed a lower contraction-frequency relationship in cyclophosphamide-treated animals. Atropine reduced the stretch(reflex)-evoked contraction by up to 50% in control and 75-80% in cyclophosphamide-treated rats. Subsequent addition of PPADS further reduced the contractions. Conclusion The micturition reflex response is increased following cyclophosphamide-induced cystitis, as compared to control. The likely cause is sensitization at mechanosensor level in the micturition arc, which overrides the decrement of the efferent cholinergic effects. Neurourol. Urodynam. 34:375-380, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim P301 S MAPT transgenic mice ( P301 S mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology ( FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301 S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood. Methods We analysed P301 S mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology. Results We confirmed the occurrence of locomotor deficits at an age of 5 months and newly report memory deficits from 2.5 months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301 S mice. Neuronal cell loss in the hippocampus of P301 S mice was not observed to occur till 6 months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones. Conclusion In P301 S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202-phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies. [ABSTRACT FROM AUTHOR]

Aims The search for new animal models to investigate both efferent and afferent levels of the micturition reflex, to better understand urinary dysfunctions, is of great importance. Therefore in this study we developed and characterized, by comparisons with a conventional whole bladder model, a novel in situ model. Methods The urinary bladder was carefully prepared and separated, via a midline incision, into two halves all the way to the urethra in pentobarbitone and medetomidine anesthetized male rats. The separated bladder halves (with no direct connection) were immobilized with ligatures to the underlying tissue. The tension could thereafter be recorded at one side, while the other half was occasionally stretched in order to evoke an afferent signal. Also, injections of ATP and methacholine and electric nerve stimulation were employed. Results Ipsilateral stretch of 30 and 50 mN induced a force-dependent contractile response on the contralateral side. Moreover, electrical stimulation of efferent pelvic nerve fibers, and intravenous injections of methacholine and ATP, evoked dose-dependent contractions, resembling responses observed in the whole bladder model. Here, the threshold frequency at electrical stimulation of the efferent fibers was <2 Hz and the maximum response appeared at 10-20 Hz, while afferent stimulation had a threshold of 5-10 Hz with the maximum response at 40 Hz. Conclusions In the current study we show that stimulation of afferents at one side of the bladder induces, via impulses from the central nervous system, contractions from the other side. This novel model enables quantitative comparisons of changes occurring within the micturition reflex arc in bladder disorders. Neurourol. Urodynam. 33:550-557, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: 5-HT1 receptor agonists have been shown to reduce abnormal involuntary movements (AIMs) in the rat and monkey models of l-DOPA-induced dyskinesia. Different mechanisms have been proposed to underlie this effect. Activation of pre-synaptic 5-HT1 receptors has been suggested to inhibit dysregulated release of dopamine from the serotonin terminals, and thus, abnormal activation of striatal dopamine receptors. Activation of post-synaptic 5-HT1 receptors expressed in non-serotonergic neurons in different brain areas, by contrast, has been shown to result in decreased glutamate and GABA release, which may also contribute to the antidyskinetic effect. To unveil the relative contribution of these mechanisms, we have investigated the effect of increasing doses of 5-HT1A and 5-HT1B receptor agonists on AIMs induced by either l-DOPA or apomorphine. In contrast to l-DOPA-induced AIMs, which were dampened already at low doses of 5-HT1 agonists, reduction of apomorphine-induced AIMs required higher doses. Removal of the serotonin innervation suppressed l-DOPA-induced AIMs, but neither affected apomorphine-induced AIMs nor the inhibiting effect of 5-HT1 agonists on AIMs induced by the direct dopamine agonist, suggesting that such effect is independent on activation of pre-synaptic 5-HT1 receptors. [Copyright &y& Elsevier]

In vivo gene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [11C]raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) enzymes using anrAAV5vector normalizes the increased [11C]raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [11C]raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D2 receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to followTH+GCH1 gene therapy in PD patientsandprovideanadditionalobjectivemeasuretoapotentialclinicaltrialusingrAAVvectorstodeliver ʟ-3,4-dihydroxyphenylanalineinthebrain. [ABSTRACT FROM AUTHOR]

Abstract: Appearance of dyskinesia is a common problem of long-term Levodopa (L-DOPA) treatment in Parkinson''s disease (PD) patients and represents a major limitation for the pharmacological management of the motor symptoms in the advanced stages of disease. An increasing body of evidence points to dopamine released as a false neurotransmitter from the striatal serotonin terminals as the main pre-synaptic determinant of L-DOPA-induced dyskinesia. Here we review the animal experimental and human clinical data in support of this view, which point to the serotonin system as a promising target for anti-dyskinetic therapy in PD patients under L-DOPA medication. [Copyright &y& Elsevier]

Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons. [ABSTRACT FROM AUTHOR]