Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.

Pharmacist comprehensive review of treatment compared with STOPP-START criteria to detect potentially inappropriate prescription in older complex patients.

OBJECTIVES: To compare potentially inappropriate prescribing (PIP) according to the clinical judgement of the pharmacist with PIP according to explicit STOPP-START criteria in institutionalised and hospitalised patients with multiple pathologies. To describe and compare the main pharmacological groups involved and determine the factors associated with the detection of PIP in these patients. METHOD: A prospective multicentre observational study of institutionalised and hospitalised multipathology patients aged >65 years. A specialised pharmacist used his best clinical judgement to detect PIP based on a comprehensive review of the complete chronic treatment of patients, which is an essential activity in interdisciplinary care. STOPP-START criteria were used as an aid tool to detect PIP. The main variable was the number of PIP incidents detected. RESULTS: Detected PIP incidents were analysed in 338 patients. Clinical judgement detected more PIP incidents (35%) than did STOPP-START criteria. More PIP incidents unrelated to these criteria were detected in institutionalised patients than in hospitalised patients. Clinical judgement mainly detected PIP incidents related to incorrect doses and drug interactions (p<0.001); however, STOPP-START criteria mainly detected PIP incidents related to drug duplication and insufficiently treated diagnosis or symptoms (p=0.001 and p<0.001). In total, 93.8% of the PIP incidents were detected in polypharmacy patients (≥5 drugs). Institutionalised and high-level polypharmacy (≥10 drugs) patients were at the highest risk of PIP. CONCLUSIONS: A large number of PIP incidents were detected in institutionalised and hospitalised patients with multiple pathologies. The inclusion of a pharmacist in the multidisciplinary team facilitated the detection of PIP incidents, particularly in the institutionalised population and patients treated with high-level polypharmacy which were not detected by explicit STOPP-START criteria.

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease.

Neuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS(+) and Phospho-Thr34-DARPP-32(+) cells, accompanied by a consequent decrease of total DARPP-32(+) cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.

Nigral degeneration correlates with persistent activation of cerebellar Purkinje cells in MPTP-treated monkeys.

In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson's disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.

IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease.

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.

Changes in vascularization in substantia nigra pars compacta of monkeys rendered parkinsonian.

The degeneration of nigral dopaminergic neurons in Parkinson's disease is believed to be associated with a glial reaction and inflammatory changes. In turn, local factors may induce changes in vascularization and contribute to neuronal vulnerability. Among these factors, Vascular Endothelial Growth Factor (VEGF) is released in adults under pathological conditions and is thought to induce angiogenesis. In order to determine whether changes in brain vasculature are observed in the affected brain regions in parkinsonism, we quantitatively analysed the VEGF-expressing cells and blood vessels in the substantia nigra of monkeys rendered parkinsonian by MPTP injection and compared the results with those obtained in control monkeys. Using stereological methods, we observed an increase in the number of VEGF-expressing neurons and an increase of the number of blood vessels and their volume occupying the substantia nigra pars compacta of monkeys rendered parkinsonian by chronic MPTP intoxication. These changes in vascularization may therefore modify the neuronal availability of blood nutrients, blood cells or toxic substances and neuronal susceptibility to parkinsonism.

[Foreign language syndrome as a first sign of multiple sclerosis]. / Sindrome del acento extranjero como primera manifestación de esclerosis múltiple.

INTRODUCTION: Foreign accent syndrome (FAS) is a little known disorder affecting language which has been described in a few cases after acute strokes or traumatic brain injuries, but until now has not been reported in multiple sclerosis (MS). It is characterised by the appearance of what is perceived to be a foreign accent in the language of the patient. Although it could be included within the dysprosodias that accompany motor aphasias, it should be considered as an entity in its own right, since it may appear without the accompanying aphasia. Aphasia is an infrequent manifestation of MS and even less so when it appears as an initial symptom of the disease. When it does occur it usually accompanies large demyelinating lesions in the dominant hemisphere, and it is usually of a motor type. CASE REPORT: Patient, aged 38 years, who presented FAS that accompanied mild non fluent aphasia as the first manifestation of MS with pseudotumoral lesions. Initially the clinical features were interpreted as a somatoform disorder, which delayed diagnosis. CONCLUSIONS: Like aphasia, FAS can occur in MS as a manifestation of a cortical language disorder. It is important to recognise this in order to prevent mistaken diagnoses.