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Summary: Vinpocetine, a derivate of vincamine, is widely used in the clinical pharmacotherapy of cerebral circulatory diseases. Herewith we report on a novel effect of vinpocetine: inhibition of retrograde axoplasmic transport of nerve growth factor (NGF) in the peripheral nerve. Blockade of retrograde transport of NGF results in transganglionic degenerative atrophy (TDA) in the segmentally related ipsilateral superficial spinal dorsal horn, which is characterized by depletion of the marker enzymes fluoride-resistant acid phosphatase (FRAP) and thiamine monophosphatase (TMP). At the same time, pain-related neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), are depleted from lamina I–III from the segmentally related, ipsilateral Rolando substance of the spinal cord. On the basis of these experiments it is suggested that vinpocetine may result in a locally restricted decrease of nociception, that might be useful in clinical treatment of intractable pain. Pilot self-experiments support this assumption. [Copyright &y& Elsevier]

Abstract: Huntington''s disease (HD) is an autosomal dominant inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin. The excitotoxicity, oxidative damage, mitochondrial dysfunction and altered membrane transport may have important roles in the pathogenesis of HD. L-carnitine plays a role in facilitating the mitochondrial transport of fatty acids, but it also protects the cells from oxidative damage. The aim of our study was to examine the effects of the intraperitoneally administered L-carnitine on the survival, behaviour and immunohistochemical changes in the N171-82Q transgenic mouse model of HD. Following L-carnitine administration the survival was improved by 14.9%. The motor activity was significantly ameliorated as compared with the control transgenic group. The L-carnitine treatment significantly reduced the neuronal loss and the number of neuronal intranuclear aggregates. These results suggest that L-carnitine may exert a neuroprotective effect by decreasing the oxidative damage. [Copyright &y& Elsevier]

Highlights • Expression of PGC- and Sirtuin isoforms was estimated after cooling and training. • 200 min cold exposure: cortical SIRT3-M1 elevated; cerebellar SIRT-M3 decreased. • 900 min cold exposure: cortical SIRT1 and striatal SIRT3-M1 decreased. • 12-day-long exercise: all PGC-1α isoform and SIRT3-M1/M2 elevated in cerebellum. • We suggest that the cerebellar changes are associated with synaptic plasticity. Abstract Proper mitochondrial function is crucial for intact cellular homeostasis. Mitochondrial dysfunction is clearly involved in the pathogenesis of most neurodegenerative- and age-related chronic disorders. The aim of this study is to stimulate cellular production of important compounds of mitochondrial biogenesis, namely in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)- and Sirtuin (SIRT)-systems. We studied the effect of cold challenge and training on the mRNA expression levels of some compounds of these systems in different brain areas of mice. With regard to the PGC-system, the mRNA levels of the full- and N-truncated isoforms, and those of the two promoters (brain-specific, reference) were measured. In case of Sirtuins, the mRNA levels of SIRT1 and SIRT3-M1/M2/M3 were assessed. We found the following expression level alterations: cooling resulted in the elevation of cortical SIRT3-M1 levels and the decrease of cerebellar SIRT3-M3 levels after 200 min. 900 min of cold exposure resulted in the reduction of cortical SIRT1 and striatal SIRT3-M1 levels. A prominent elevation could be observed in the levels of all PGC-1α isoforms in the cerebellum after 12 days of training. The 12 days of exercise resulted in increased cerebellar SIRT3-M1 and SIRT3-M2 mRNA levels as well. Although the efficacy of cooling core body and brain temperature is questionable, we found that training exerted a clear effect. The cause of the prominent cerebellar elevation of PGC-, and Sirtuin isoforms could be an increase in synaptic plasticity between Purkinje cells, which facilitates better motor coordination and more precise movement integration. We propose that these systems may serve as promising targets for future therapeutic studies in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Corroborating with prior experimental findings, we recently reported the pronounced elevation of peroxisome proliferator-activated receptor gamma (PPARγ) protein concentration in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), in association with neuroinflammatory markers and clinical severity. Based on subsequent reports on the possible involvement of other PPARs and PPARγ coactivator-1alpha (PGC-1α) in neuroinflammation in MS, we analyzed the protein levels of PPARα, PPARβ/δ, and PGC-1α in a subset of CSF samples from the same cohort of relapsing-remitting MS patients. Unlike PPARγ, none of these proteins were found elevated in MS patients (n = 25) compared to non-inflammatory controls (n = 16), with the levels of PPARα and PPARβ/δ found generally below the limit of detection, and that of PGC-1α being detectable but comparable in both groups. The clinical and laboratory associations previously reported with PPARγ were however significant even in this smaller subset. The potential underlying causes of these differential alterations are discussed. The findings suggest that despite their proposed involvement in the regulation of inflammatory processes in MS, PPARα, PPARβ/δ, and PGC-1α proteins are not potential biomarkers of neuroinflammation in MS, and indicate a preferential role of PPARγ in the endogenous regulation of autoimmune response in the human CNS within its receptor family. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Besides the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). Achieving neuroprotection via CNS-targeted pharmacological stimulation is limited due to poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option. The current study aimed to examine of how the expression levels of FL-, NT-, CNS- and reference PGC-1α isoforms change in different brain regions following various 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment regimens, including chronic low-dose treatment for preconditioning. Ninety minutes following the acute treatment regimen, the expression levels of FL-, NT- and CNS-PGC-1α isoforms increased significantly in the striatum, cortex and cerebellum. However, this elevation diminished 7 days following the last MPTP injection in the acute treatment regimen. The chronic low-dose administration of MPTP, which did not cause significant toxic effects in light of the relatively unaltered dopamine levels, did not result in any significant change of PGC-1α expression. The elevation of PGC-1α levels following acute treatment may demonstrate a short-term compensatory mechanism against mitochondrial damage induced by the complex I inhibitor MPTP. However, drug-induced preconditioning by chronic low-dose MPTP seems not to induce protective responses via the PGC-1α system. [ABSTRACT FROM AUTHOR]

Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington’s disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases. [ABSTRACT FROM AUTHOR]

Kynurenic acid (KYNA) is a neuroactive metabolite that interacts with NMDA, AMPA/kainate and alpha 7 nicotinic receptors. The goal of this study was to clarify the roles of these receptors in the action of KYNA at a spinal level by using highly specific receptor antagonists alone or in triple combinations. Chronic osteoarthritis-like joint pain was induced with monosodium-iodoacetate in male Wistar rats. Mechanical allodynia and motor function were quantified. In the first series we determined the dose–response and time course effects of intrathecally administered KYNA (10–100 μg), d -(−)-2-amino-5-phosphonopentanoic acid (AP5; an NMDA receptor antagonist; 10–200 μg), methyllycaconitine (MLA; an alpha 7 nicotinic receptor antagonist; 100–200 μg) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX; an AMPA/kainate receptor antagonist; 1–20 μg). In the second series, four different triple combinations of MLA, AP5 and NBQX were investigated. Intrathecal administration of KYNA caused a dose-dependent motor impairment and antinociception. The highly specific NMDA receptor antagonist AP5 caused a motor impairment and antinociception with lower potency. High doses of NBQX resulted in significant antinociception with a slight motor impairment, while only the highest dose of MLA gave rise to significant antinociception with a slight motor impairment. After the coadministration of these ligands as combinations, no potentiation was observed. It may be supposed that the effects of KYNA are primarily due to the inhibition of NMDA receptors at both glycine and phencyclidine (PCP) binding sites, and not to the interactions at the different ionotropic receptors, but the mechanisms behind its high bio-efficiency are still unknown. [ABSTRACT FROM AUTHOR]

Highlights: [•] PPAR-gamma level is elevated in the cerebrospinal fluid of patients with multiple sclerosis. [•] PPAR-gamma level in the cerebrospinal fluid strongly correlates with cell count and IgG index. [•] PPAR-gamma level in the cerebrospinal fluid shows positive association with clinical severity. [ABSTRACT FROM AUTHOR]

Highlights: [•] Genotyping for four polymorphic sites in the VDR gene in patients with Parkinson's disease. [•] Association was detected between FokI C polymorphism and Parkinson's disease. [•] No association could be detected between ApaI, BsmI, TaqI polymorphisms and Parkinson's disease. [Copyright &y& Elsevier]

Abstract: Biomarkers capable of predicting the clinical course and the rate of disease progression in multiple sclerosis are currently unavailable. Our objective was to examine if the levels of proteins associated with axonal and neuronal degeneration (Tau, p-Tau and β-amyloid1-42) and T-cell-mediated autoimmunity (osteopontin) are altered in the cerebrospinal fluid (CSF) of MS patients, and to assess their potential in reflecting the clinical severity and predicting the progression and clinical evolution of early MS. The CSF samples collected from patients presenting with different clinical forms of MS were evaluated by enzyme-linked immunosorbent assays. The patients were regularly followed-up and their clinical status was re-evaluated 5years after sampling. The results demonstrated that while CSF levels of Tau, p-Tau and β-amyloid1-42 did not differ between MS and Control groups, the levels of osteopontin were significantly elevated in MS patients. This increase was associated with the presence of a relapse and correlated with clinical severity, which findings were independent of age and blood–CSF barrier function. However, none of the examined protein levels differed significantly between groups with different clinical evolutions and no positive correlations with clinical progression could be detected. We conclude that Tau, p-Tau and β-amyloid1-42 are inappropriate as biomarkers in MS. This is the first report on CSF osteopontin as an independent marker of clinical severity in definite MS. [Copyright &y& Elsevier]

Abstract: The nitric oxide donor, nitroglycerin (NTG) can trigger a migraine attack, after a delay of several hours in migraineurs, but not in healthy people. This long delay does not favor a pure vasodilatatory action. In rats, subcutaneous administration of NTG (10mg/kg) significantly and selectively increases the number of calmodulin-dependent protein kinase II alpha (CamKIIα)-immunoreactive neurons in the trigeminal caudal nucleus (TNC) after 4h. The aim of our study was to determine if any isoforms of the cyclooxygenase (COX) enzyme might have a role in the NTG-induced increase of CamKIIα expression. In our experiments, we demonstrated that pretreatment with NS398, the selective COX-2 inhibitor attenuated the NTG-induced CamKIIα expression in the TNC at doses of 3 and 5mg/kg. In contrast, SC560, a selective COX-1 inhibitor failed to modulate this phenomenon in any of the dosages used (1, 5 and 10mg/kg). These findings suggest that COX-2, but not COX-1 derived metabolites are important factors in the NTG-induced CamKIIα expression. Thus this isoform may play a significant role in the induction of migraine. These data could help in the better understanding of the pathogenesis of headaches and the action of antimigraine drugs. [Copyright &y& Elsevier]