Neurobiology of disease
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Neurobiology of disease · Jan 2012
In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to L-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels.
Evidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or D2 receptor blockade on abnormal involuntary movements (AIMs) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. ⋯ In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum.
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Neurobiology of disease · Jan 2012
Nerve growth factor/p38 signaling increases intraepidermal nerve fiber densities in painful neuropathy of type 2 diabetes.
Painful diabetic neuropathy (PDN) is a common, yet devastating complication of type 2 diabetes. At this time, there is no objective test for diagnosing PDN. In the current study, we measured the peptidergic intraepidermal nerve fiber densities (IENFD) from hind paws of the db/db mouse, an animal model for type 2 diabetes, during the period of mechanical allodynia from 6 to 12 weeks of age. ⋯ In addition, SB203580, an inhibitor of p38, blocked the increase in peptidergic IENFD in db/db mice. The current results suggest that peptidergic IENFD could be a potential diagnostic indicator for PDN in type 2 diabetes. Furthermore, the inhibition of NGF-p38 signaling could be a potential therapeutic strategy for treating this painful condition.
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Neurobiology of disease · Jan 2012
In vitro drug treatments reduce the deleterious effects of aggregates containing polyAla expanded PHOX2B proteins.
Heterozygous in frame duplications of the PHOX2B gene, leading to polyalanine (polyAla) expansions ranging from +5 to +13 residues of a 20-alanine stretch, have been identified in the vast majority of patients affected with Congenital Central Hypoventilation Syndrome (CCHS), a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Ventilatory supports such as tracheostomy, nasal mask or diaphragm pacing represent the only options available for affected. We have already shown that the severity of the CCHS phenotype correlates with the length of polyAla expansions, ultimately leading to formation of toxic intracytoplasmic aggregates and impaired PHOX2B mediated transactivation of target gene promoters, such as DBH. ⋯ In this work, we have undertaken in vitro analyses aimed at assessing the effects of molecules on the cellular response to polyAla PHOX2B aggregates. In particular, we tested 17-AAG, ibuprofen, 4-PBA, curcumin, trehalose, congo red and chrysamine G for their ability to i) recover the nuclear localisation of polyAla expanded PHOX2B, ii) rescue of PHOX2B mediated transactivation of the DBH promoter, and iii) clearance of PHOX2B (+13 Ala) aggregates. Our data have suggested that 17-AAG and curcumin are effective in vitro in both rescuing the nuclear localization and transactivation activity of PHOX2B carrying the largest expansion of polyAla and promoting the clearance of aggregates of these mutant proteins inducing molecular mechanisms such as ubiquitin-proteasome (UPS), autophagy and heat shock protein (HSP) systems.
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Neurobiology of disease · Jan 2012
Core features of frontotemporal dementia recapitulated in progranulin knockout mice.
Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. ⋯ Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.
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Neurobiology of disease · Jan 2012
A30P α-synuclein impairs dopaminergic fiber regeneration and interacts with L-DOPA replacement in MPTP-treated mice.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc). α-synuclein (αsyn) has been linked to the pathophysiology of PD, because of its mutations causing familial PD and its accumulation in brains of patients with familial and sporadic PD. Dopamine (DA) replacement is the most effective therapy for ameliorating the motor symptoms of PD; however, it remains controversial whether DA-replacement boosts regeneration in the dopaminergic system or accelerates disease progression and enhances neuronal loss. Here, we studied the effect of chronic L-DOPA treatment on dopaminergic neurons in wild-type (WT) and A30P αsyn transgenic mice after MPTP treatment. ⋯ In contrast, regeneration was less pronounced in A30P αsyn mice. Chronic L-DOPA treatment after MPTP intoxication did not only reduce the regeneration of nigrostriatal fibers but also led to an increased apoptotic gene-expression profile in the SNpc and to a decline of TH-positive neurons in A30P αsyn. Our findings reveal that the presence of A30P αsyn inhibits the regeneration of nigrostriatal dopaminergic fibers, and that L-DOPA treatment might interact with the pathogenesis in PD.