Objectives – While clinical hypothyroidism is associated with frank neuropsychological and affective alterations and is considered one of the causes of reversible dementia, the occurrence of these ...alterations and their treatment in mild hypothyroidism (MH) remains a controversial issue. Our aim was therefore to evaluate cognitive and psychological functions in a selected population of recently‐diagnosed MH patients with minor subjective symptoms.
Materials and methods – Thirty‐six MH women (mean age 51.9 ± 13.5 years) were observed after a careful assessment had excluded subjects with neurological, psychiatric and/or somatic disorders, or confounding conditions. The subjects were evaluated for thyroid function and tested with an extensive battery of neuropsychological tests and psychological rating scales, in basal conditions and after 6 months of l‐thyroxine treatment.
Results – Baseline neuropsychological performance was within the normal range, while an age‐dependent reduction was found in attentive function. After l‐thyroxine treatment, an increase in serum fT4 was detected in parallel with thyroid stimulating hormone (TSH) reduction. Verbal fluency and depression scores showed a slight improvement. A positive correlation was found between TSH reduction and improved mood scores.
Conclusion – From the analysis of the results, treatment of asymptomatic MH would seem advisable in order to re‐set hormonal levels and, particularly in older subjects, to protect the brain against the potential risk of cognitive and affective dysfunctions.
CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the ...electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.
Abstract Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry ...of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) – which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine – are associated with a wide range of clinical manifestations, mostly affecting the central nervous system ( e.g. , mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l -Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.
Chronic reduction of the caloric intake is associated with extended lifespan, in rodents, and has been proposed to counteract neuronal loss in animal models of neurodegeneration. To test this ...hypothesis, we investigated the effect of dietary restriction (DR) in a rodent model of Parkinson's disease, based on the intrastriatal infusion of 6-hydroxydopamine. We could not confirm the neuroprotective effect of DR previously suggested: histological and behavioral measures indicated similar degrees of dopaminergic neuron loss in rats maintained on DR – for two or eight weeks prior to the lesion – or with free access to food.
Abstract Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been ...reported in fibroblasts of GBA1 -mutant PD patients and pharmacological chaperone ambroxol has been shown to correct such defect. To further explore this issue, we investigated GCase and elements supporting GCase function and trafficking in fibroblasts from sporadic PD patients — with or without heterozygous GBA1 mutations — and healthy subjects, in basal conditions and following in vitro exposure to ambroxol. We assessed protein levels of GCase, lysosomal integral membrane protein-2 (LIMP-2), which mediates GCase trafficking to lysosomes, GCase endogenous activator saposin (Sap) C and parkin, which is involved in degradation of defective GCase. We also measured activities of GCase and cathepsin D, which cleaves Sap C from precursor prosaposin. GCase activity was reduced in fibroblasts from GBA1 -mutant patients and ambroxol corrected this defect. Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups, while LIMP-2 levels were increased only in GBA1 -mutant PD fibroblasts. Parkin levels were slightly increased only in the PD group without GBA1 mutations and were not significantly modified by ambroxol. Our study confirms that GCase activity is deficient in fibroblasts of GBA1 -mutant PD patients and that ambroxol corrects this defect. The drug increased Sap C and LIMP-2 protein levels, without interfering with parkin. These results confirm that chemical chaperone ambroxol modulates lysosomal markers, further highlighting targets that may be exploited for innovative PD therapeutic strategies.
Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been implicated in the generation and modulation of pain. To investigate whether alterations in ...neurotrophin levels can be detected in subjects suffering from nociceptive disorders, such as primary headaches, we determined the peripheral (platelet and plasma) levels of BDNF and NGF in patients suffering from migraine, with or without aura, or cluster headache (CH), in the interictal phase, and in healthy volunteers. All primary headaches patients studied showed significantly decreased platelet levels of BDNF (migraine vs. controls P < 0.001; CH vs. controls P < 0.01), while a selective reduction of platelet NGF was observed in migraine sufferers and not in CH patients compared with control subjects (migraine vs. controls P < 0.001). These changes were not accompanied by significant modifications of neurotrophin plasma levels. Our findings show for the first time that changes in peripheral levels of neurotrophines (BDNF and NGF) occur in patients suffering from different types of primary headaches, suggesting a potential involvement of BDNF and NGF in the pathophysiology of these disorders, and raising the possibility that differences in peripheral neurotrophins may help to distinguish migraine biologically from CH.
Abstract The origin recognition complex (ORC) regulates DNA replication. However, some members of the ORC core, such as ORC3 and ORC5, have been implicated in neuronal maturation. In cultured ...cerebellar granule cells (CGCs), ORC3 mRNA and protein levels increased from 6 to 8 days in vitro , a time that coincided with the maximal development of the dendritic arbor. In contrast, expression of ORC5 remained low throughout CGC maturation. Activation of type-4 metabotropic glutamate receptors with the selective enhancer, PHCCC, during a critical time-window (from 4 to 6 days in vitro ) anticipated the developmental peak of ORC3, increased the expression of two proteins associated with neuronal maturation, i.e. the mitogen-associated protein-2 (MAP-2) and postsynaptic density-95 (PSD-95), as well as dendritic length. siRNA-induced ORC3 knockdown reduced MAP-2 and PSD-95 expression on its own and abrogated the action of PHCCC. We examined whether the maturational effects of ORC3 were mediated by changes in the activity of the monomeric GTP-binding protein, Rho, which is known to regulate granule cell morphology. ORC3 knockdown increased the levels of the GTP-bound active form of Rho, whereas exposure to PHCCC reduced Rho activation. The action of PHCCC was largely attenuated in cultures deprived of ORC3. Finally, granule cell exposure to the Rho-associated kinase inhibitor, Y-27632, abolished the lowering effect of ORC3 knockdown on MAP-2 expression, and increased dendritic length. These data suggest that ORC3 supports neuronal maturation by inhibiting the Rho signaling pathway, and mediates the differentiating activity of mGlu4 receptors in cultured cerebellar granule cells.
Although the involvement of nitric oxide (NO) in mediating pain and neurovascular coupling is well established, the precise mechanisms sustaining these effects are still unclear. Cyclic GMP (cGMP) ...probably represents the main effector of the biological effects of NO at the vascular and neuronal levels. Nitroglycerin is a NO donor, which easily crosses the blood brain barrier. Several reports have suggested that the study of nitroglycerin effects upon neuronal and cerebrovascular elements is a useful animal model for investigating the pathophysiological mechanisms underlying migraine. In this study, the anatomic distribution of cGMP in the rat brain was evaluated at serial time-points after systemic administration of nitroglycerin or vehicle. The results show an increase in cGMP immunoreactivity in the nucleus trigeminalis caudalis and in the superficial cortical arterioles 2, 3 and 4
h after the drug administration. The data obtained sustains the idea that cGMP is an important mediator of nitroglycerin effect in vascular and neuronal structures that are critical elements for the transmission of cephalic pain.
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