Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.     

Nerve growth factor and chronic daily headache: a potential implication for therapy

The pivotal role of nerve growth factor in inducing hyperalgesia and central sensitization has been emphasized in experimental pain models. Higher nerve growth factor levels have recently been found in the cerebrospinal fluid of patients with chronic daily headache. These levels were significantly correlated with the cerebrospinal fluid levels of substance P and calcitonin gene-related peptide, supporting the involvement of this neurotrophin in enhancing the production of the two sensory neuropeptides of the trigemino-vascular system in chronic daily headache. This may, in part, account for the long-lasting sensitization and activation of this system, which could contribute to headache chronicity. More recent research has shown a significant correlation between the higher cerebrospinal fluid levels of nerve growth factor and those of another neurotrophin, the brain-derived neurotrophic factor, as well as glutamate in chronic daily headache patients. These findings suggest the potential involvement of nerve growth factor-mediated upregulation of brain-derived neurotrophic factor in persistent head pain. Therefore, nerve growth factor appears to indirectly exert its effect through enhancing glutamatergic transmission involved in the processing of head pain via brain-derived neurotrophic factor. Based on these data, a potential application can be hypothesized for novel strategies targeting neurotrophins (nerve growth factor and brain-derived neurotrophic factor) and their receptors to chronic daily headache. To date, the majority of the molecules discovered in this regard have been scarcely or never proved in animal pain models and are far from clinical use in chronic pain, including chronic daily headache. If this approach is to be developed in the near future, research should be focused on identifying strategies with few central side effects and specific selective action on central sites involved in chronic head pain and more generally in chronic pain conditions. This will represent a very difficult challenge, taking into account the pleiotropic effect of nerve growth factor and the wide range of intracellular signalling pathways activated by this neurotrophin which are not limited to the nociceptive system.     

Combined pharmacotherapy and psychological treatment for depression: a systematic review

BACKGROUND: Adherence to antidepressant medication use is a problem in clinical practice. Some authors have posited that combined psychological treatment facilitates adherence to pharmacotherapy. OBJECTIVES: To study the relationship between adherence to use of and efficacy of antidepressant drugs plus psychological treatment vs drug treatment alone in depressive disorders. DATA SOURCES: MEDLINE, Current Contents, PsychInfo, Cochrane Library, and reference lists were searched, from January 1980 to November 2002. STUDY SELECTION: Randomized clinical trials comparing antidepressant treatment alone with antidepressant treatment in combination with a psychological intervention in depressive disorders were considered. The decision to include studies in the meta-analysis was performed by 2 reviewers. DATA EXTRACTION: Three independent reviewers extracted the data, using a precoded form. Methodological quality of the studies was evaluated in terms of allocation concealment and independence of evaluators. DATA SYNTHESIS: Sixteen trials met the inclusion criteria, with 932 patients randomized to pharmacotherapy alone and 910 to combined treatment. Overall, patients receiving combined treatment improved significantly compared with those receiving drug treatment alone (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.38-2.52), but dropouts and nonresponders did not differ in distribution between the 2 treatment modalities (OR, 0.86; 95% CI, 0.60-1.24). Studies longer than 12 weeks showed a significant advantage of combined treatment over drug treatment alone (OR, 2.21; 95% CI, 1.22-4.03), with a significant reduction in dropouts compared with nonresponders (OR, 0.59; 95% CI, 0.39-0.88). These estimates were not affected by study quality. CONCLUSIONS: Psychological treatment combined with antidepressant therapy is associated with a higher improvement rate than drug treatment alone. In longer therapies, the addition of psychotherapy helps to keep patients in treatment. Further studies are needed to investigate whether the improvement in response attributable to the combination of drug treatment and psychotherapy can be achieved by a combination of pharmacotherapy and a compliance-enhancing intervention.     

Relationship between stress and circulating levels of S100B protein

It has been proposed that S100B can be a marker for several pathological conditions including brain traumas, blood-brain barrier disruption, and ischemia. Because the hypothalamo-pituitary-adrenal axis is activated in these conditions, we investigated the role of glucocorticoids in the effects of stress on serum S100B. Restraint stress increased S100B levels in control and in adrenalectomized but not in corticosterone-injected rats. Adrenalectomy did not alter basal S100B. These results indicate a glucocorticoid-independent relationship between stress and S100B.     

Effects of long-term exposure of lemon essential oil odor on behavioral, hormonal and neuronal parameters in male and female rats

Behavioral, hormonal and neuronal responses to prolonged exposure to the volatile components of essential oil (EO) extracted from citrus lemon were investigated in male and female rats. Animals were exposed to the lemon essence for 2 weeks while in their cage. Anxiety was then determined with the elevated plus-maze apparatus while nociception was evaluated with a phasic thermal pain stimulus (plantar test) and with a chemical pain stimulus (formalin test). At the end of the experimental sessions, brain areas were dissected to measure beta-endorphin (beta-EP) concentrations in the hypothalamus and periaqueductal gray matter (PAG). Blood samples were collected to determine corticosterone plasma levels. In both sexes, prolonged EO exposure decreased the time spent in the open arms of the plus-maze apparatus. EO-exposed males and females showed higher thermal nociceptive thresholds than controls when tested with the plantar test apparatus. EO exposure induced female-specific decreases in formalin-induced pain behaviors during the formalin test. beta-EP concentrations in the hypothalamus and PAG were affected by EO. Corticosterone was lower in EO-exposed animals of both sexes than in their controls. These results suggest that long-term exposure to lemon EO can induce significant, at times sex-specific, changes in neuronal circuits involved in anxiety and pain.     

Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine

PURPOSE: Alterations in neuronal calcium (Ca2+) homeostasis are believed to play an essential role in the generation and propagation of epileptiform events. Levetiracetam (LEV) and lamotrigine (LTG), novel antiepileptic drugs (AEDs), were tested on epileptiform events and the corresponding elevations in intracellular Ca2+ concentration ([Ca2+]i) recorded from rat neocortical slices. METHODS: Electrophysiological recordings were performed from single pyramidal neurons from a slice preparation. Spontaneous epileptiform events consisting of long-lasting, repetitive paroxysmal depolarization shifts (PDSs) and interictal spike activity were induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. Simultaneously, microfluorimetric measurements of [Ca2+]i were performed. Optical imaging with Ca2+ indicators revealed a close correlation between Ca2+ transients and epileptiform events. RESULTS: Both LEV and LTG were able to reduce both amplitude and duration of PDSs, as well as the concomitant elevation in [Ca2+]i, in a dose-dependent fashion. Whole-cell patch-clamp recordings from isolated neocortical neurons revealed that LEV significantly reduced N-, and partially P/Q-type high-voltage-activated (HVA) Ca2+ currents, whereas sodium currents were unaffected. Interestingly, the inhibitory effects of LEV were mimicked and occluded by LTG or by a combination of omega-conotoxin GVIA and omega-agatoxin IVA, selective blockers of N- and P/Q-type HVA channels, respectively, suggesting a common site of action for these AEDs. CONCLUSIONS: These results demonstrate that large, transient elevations in neuronal [Ca2+]i correlate to epileptiform discharges. The antagonistic effects of LEV and LTG on [Ca2+]i overload might represent the basis for their anticonvulsant efficacy and could preserve neuronal viability.     

Nicotinic acetylcholine receptor subtypes in the rat sympathetic ganglion: pharmacological characterization, subcellular distribution and effect of pre- and postganglionic nerve crush

Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission in autonomic ganglia, which innervate and control the activity of most visceral organs. By combining ultrastructural, immunocytochemical, and pharmacological analyses, we characterized the nAChR subtypes in the rat superior cervical ganglion (SCG) and the effect of pre- and postganglionic nerve crush on their number in the ganglion and their distribution at the intraganglionic synapses. Binding with radioactive nicotinic ligands, immunoprecipitation, and immunolocalization experiments revealed the presence of different nAChR subtypes: those containing the alpha3 subunit associated with beta4 and/or beta2 subunits that bind 3H-Epibatidine with high affinity, and those containing the alpha7 subunit that bind 125I-alphaBungarotoxin. After postganglionic nerve crush, the number of nicotinic receptors and immunopositive intraganglionic synapses for each nAChR subunit strongly decreased. Both the number of nAChRs and immunoreactivity recovered 26 days after injury, when regenerating postganglionic fibers had reinnervated the peripheral target organs, as shown by the restoration of tyrosine hydroxylase immunoreactivity in the iris. This observation and the lack of any effect of preganglionic nerve crush on the number of nicotinic receptors suggest that the peripheral targets affect the organization of intraganglionic synapses in adult SCG.     

Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study

OBJECTIVE: The gross morphology and morphometry of the hippocampus, fornix, and corpus callosum in patients with severe non-missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions was examined and the volumes of these structures were correlated with performance on memory tests. In addition, the predictability of the length of coma from the selected anatomical volumes was examined. METHOD: High spatial resolution T1 weighted MRI scans of the brain (1 mm3) and neuropsychological evaluations with standardised tests were performed at least 3 months after trauma in 19 patients. RESULTS: In comparison with control subjects matched in terms of gender and age, volume reduction in the hippocampus, fornix, and corpus callosum of the nmTBI patients was quantitatively significant. The length of coma correlated with the volume reduction in the corpus callosum. Immediate free recall of word lists correlated with the volume of the fornix and the corpus callosum. Delayed recall of word lists and immediate recall of the Rey figure both correlated with the volume of the fornix. Delayed recall of the Rey figure correlated with the volume of the fornix and the right hippocampus. CONCLUSION: These findings demonstrate that in severe nmTBI without obvious neuroradiological lesions there is a clear hippocampal, fornix, and callosal volume reduction. The length of coma predicts the callosal volume reduction, which could be considered a marker of the severity of axonal loss. A few memory test scores correlated with the volumes of the selected anatomical structures. This relationship with memory performance may reflect the diffuse nature of the damage, leading to the disruption of neural circuits at multiple levels and the progressive neural degeneration occurring in TBI.     

Action observation and speech production: study on children and adults

The present study aimed to determine whether observation of upper limb actions selectively influences speech production. We compared the effects on children with those on adults, hypothesizing that action observation is used by children for speech learning. Children and adults observed an actor either grasping a cherry or an apple, or bringing the same fruits to his mouth. They pronounced the syllable/ba/ at the end of the action. In a control experiment, children and adults executed the two bringing-to-the-mouth actions, still pronouncing/ba/. As previously found ([Euro. J. Neurosci., 17 (2003) 179]; [Euro. J. Neurosci., 19 (2004) 192]), the observed kinematics of the action, which were different according to the fruit size, influenced lip shaping kinematics and voice formants. In addition, the effect was selective for the action since the observations of actions such as grasping and bringing-to-the-mouth affected formant 1 and formant 2 in the voice spectra, respectively. The effects on speech were greater in the children than in the adults. By contrast, the effects on lip shaping did not differ between the two groups. Effects similar to those found for action observation were found for action execution in spite of a different arm kinematics between children and adults. The results of the present study are discussed according to the hypothesis that action observation induces in the viewer action recognition and activation of the successive mouth act (probably grasping-with-the-mouth when observing grasping-with-the-hand and chewing when observing bringing-to-the-mouth). This subsequently seems to affect characteristics peculiar to the emitted vowel. This mechanism might have been used by humans to transfer a primitive arm gesture communication system from the arm to the mouth and may be further used by children for speech learning.