Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction

Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC₅₀ value of 16.38 μM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC₅₀ value of 32.5 μM.Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 μM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity.Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.     

Role of NMDA receptor in homocysteine-induced activation of Mitogen-Activated Protein Kinase and Phosphatidyl Inositol 3-Kinase pathways in cultured human vascular smooth muscle cells

Introduction

Exposure of vascular smooth muscle cells (VSMC) to homocysteine, at concentrations associated with an increased risk of cardiovascular events, enhances synthesis and secretion of Matrix Metalloproteinase-2 (MMP-2), which is involved in atherosclerotic plaque instabilization. This effect was prevented by inhibitors of Mitogen Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3-K) pathways, allowing to hypothesize that homocysteine activates both these pathways, likely via a receptor-mediated mechanism. One possible receptor is N-methyl-D-aspartate receptor (NMDAr), which is expressed in VSMC and is involved in homocysteine effects in other cell types.

Materials and Methods

VSMC exposed to DL-homocysteine or NMDA (100 μmol/L for both; 5 min-8 hours), were investigated by measuring: i) phosphorylation of ERK1/2, p38MAPK (signaling molecules of MAPK pathway) and Akt and p70S6K (signaling molecules of PI3-K pathway) by western blot; ii) synthesis and secretion of MMP-2 (western blot); iii) activation of MMP-2 (gelatin zimography). To evaluate NMDAr involvement in the homocysteine effects, the experiments were repeated in the presence of a non-competitive NMDAr-antagonist MK-801 (50 μmol/L) or L-glycine (10 μmol/L), which inhibits NMDAr function by promoting its internalization.

Results

DL-homocysteine and NMDA time-dependently increased: i) the phosphorylation of ERK1/2, p38 MAPK, Akt and p70S6K (ANOVA, p < 0.0001); ii) the synthesis, secretion and activation of MMP-2. DL-homocysteine and NMDA effects were prevented by VSMC pre-incubation with MK-801 or high L-glycine concentrations.

Conclusions

In human VSMC homocysteine-at concentrations associated with increased cardiovascular risk- activates MAPK and PI3-K pathways and MMP-2 synthesis and secretion through NMDA receptor, a potential mechanism involved in intracellular signaling in response to homocysteine in VSMC.     

Everyday use of the computer mouse extends peripersonal space representation

Auditory and tactile stimuli are integrated within a limited space around the body to form an auditory peripersonal space (APPS). Here we investigate whether the APPS representation around the hand can be extended through the use of a common technological tool such as the computer mouse. When using a mouse, an action occurring in the space around the hand has a distal effect in the space defined by the computer screen; thus, the mouse virtually links near and far space. Does prolonged experience with the mouse durably extend APPS representation to the far space? We examined 16 habitual mouse users to determine whether a sound presented near the right hand or near the computer screen affected reaction times to a tactile target at the hand. When subjects sat in front of the computer, without holding the mouse, they responded faster to tactile stimuli when sounds were presented near the hand rather than near the screen, consistent with a normal segregation of APPS around the hand. In contrast, when subjects either actively used or even passively held the mouse, the difference between the effects of near and far sounds disappeared, thus showing an extension of the APPS toward the far space. This effect was selective for the effector used to operate the mouse: if tactile stimuli were presented on the left hand, rarely used to act upon the mouse, a sound presented near the hand speeded up reactions times when subjects both held and did not hold the mouse in their left hand.     

Improving language without words: first evidence from aphasia

The pervasiveness of word-finding difficulties in aphasia has motivated several theories regarding management of the deficit and its effectiveness. Recently, the hypothesis was advanced that instead of simply accompanying speech gestures participate in language production by increasing the semantic activation of words grounded in sensory-motor features, hence facilitating retrieval of the word form. Based on this assumption, several studies have developed rehabilitation therapies in which the use of gestures reinforces word recovery. Until now, however, no studies have investigated the beneficial effects of gesture observation in word retrieval.Here, we report whether a different modality of accessing action-motor representation interacts with language by promoting long lasting recovery of verb retrieval deficits in aphasic patients.Six aphasic participants with a selective deficit in verb retrieval participated in an intensive rehabilitation training that included three daily sessions over two consecutive weeks. Each session corresponded to a different rehabilitation procedure: (1) “action observation”, (2) “action observation and execution”, and (3) “action observation and meaningless movement”. In the four participants with lexical phonologically based disturbances, significant improvement of verb retrieval was found only with “action observation” and “action observation and execution”. No significant differences were present between the two procedures. Moreover, the follow-up testing revealed long-term verb recovery that was still present two months after the two treatments ended.In support of a multimodal representation of action, these findings univocally demonstrate that gestures interact with the speech production system, inducing long-lasting modification at the lexical level in patients with cerebral damage.     

Cortical connections of the visuomotor parietooccipital area V6Ad of the macaque monkey

Area V6A, a functionally defined region in the anterior bank of the parietooccipital sulcus, has been subdivided into dorsal and ventral cytoarchitectonic fields (V6Ad and V6Av). The aim of this study was to define the cortical connections of the cytoarchitectonic field V6Ad. Retrograde and bidirectional neuronal tracers were injected into the dorsal part of the anterior bank of parietooccipital sulcus of seven macaque monkeys (Macaca fascicularis). The limits of injection sites were compared with those of cytoarchitectonic fields. The major connections of V6Ad were with areas of the superior parietal lobule. The densest labeling was observed in the medial intraparietal area (MIP). Areas PEc, PGm, and V6Av were also strongly connected. Labeled cells were found in medial parietal area 31; in cingulate area 23; in the anterior (AIP), ventral (VIP), and lateral (LIP) intraparietal areas; in the inferior parietal lobule (fields Opt and PG); and in the medial superior temporal area (MST). In the frontal lobe, the main projection originated from F2, although labeled cells were also found in F7 and area 46. Preliminary results obtained from injections in nearby areas PEc and V6Av revealed connections different from those of V6Ad. In agreement with functional data, the strong connections with areas where arm‐reaching activity is represented suggest that V6Ad is part of a parietofrontal circuit involved in the control of prehension, and connections with AIP specifically support an involvement in the control of grasping. Connections with areas LIP and Opt are likely related to the oculomotor activities observed in V6Ad. J. Comp. Neurol. 513:622–642, 2009. © 2009 Wiley‐Liss, Inc.     

Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti-core antibodies may develop overt " de novo " HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O-HBV). In the native liver, 8/30 patients had detectable O-HBV; during the follow-up, O-HBV infection was demonstrated in 14 graft specimens. Graft O-HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O-HBV and no O-HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post-transplant O-HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O-HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.     

Bleomycin-Based Electrochemotherapy: Clinical Outcome from a Single Institution’s Experience with 52 Patients

Electrochemotherapy (ECT) has emerged as a complementary treatment for superficial metastases. Fifty-two consecutive patients with different cancer histotypes, mainly melanoma and breast cancer, with disease unsuitable for conventional treatments underwent bleomycin-based ECT for cutaneous and subcutaneous metastases. Toxicity, local response, response duration, and the impact on quality of life were evaluated. A total of 608 tumor nodules were treated (mean, 12 per patient), with 27% of patients affected by nodules >3 cm in size. Treatment was tolerated well, especially under general sedation. An objective response was obtained in 50 (96%) of 52 patients 1 month after the first application. Twenty-two patients underwent a second treatment (because of partial response or the appearance of new lesions). Partial response at first ECT achieved a response consolidation at second application: 80% complete response, 20% partial response. Some patients underwent up to five treatments because of new lesions, but maintained superficial tumor control. After a mean follow-up of 9 (range, 2–21) months, only two patients experienced relapse in the treatment field. Through a nonvalidated eight-item questionnaire (assessing wound healing and bleeding, aesthetic impairment, daily activities, social relations, pain, treatment satisfaction, acceptance of retreatment), most patients reported a benefit in local disease-related complaints and in activity of daily living. In a palliative setting, ECT proved to be safe, effective in all tumors treated, and useful in preserving patients’ quality of life. This benefit, although preliminary, deserves further assessment after a formal validation of the dedicated questionnaire.     

A microswitch-cluster program to foster adaptive responses and head control in students with multiple disabilities: replication and validation assessment

A program relying on microswitch clusters (i.e., combinations of microswitches) and preferred stimuli was recently developed to foster adaptive responses and head control in persons with multiple disabilities. In the last version of this program, preferred stimuli (a) are scheduled for adaptive responses occurring in combination with head control (i.e., head upright) and (b) last through the scheduled time only if head control is maintained for that time. The first of the present two studies was aimed at replicating this program with three new participants with multiple disabilities adding to the three reported by Lancioni et al. [Lancioni, G. E., Singh, N. N., O'Reilly, M. F., Sigafoos, J., Didden, R., Oliva, D., et al. (2007). Fostering adaptive responses and head control in students with multiple disabilities through a microswitch-based program: Follow-up assessment and program revision. Research in Developmental Disabilities, 28, 187-196]. The second of the two studies served to carry out an expert validation of the program's effects on head control and general physical condition with the three participants of Study I as well as the three participants involved in the Lancioni et al. study mentioned above. The expert raters were 72 new physiotherapists and 72 experienced physiotherapists. The results of Study I supported previous data and indicated that the program was effective in helping the participants increase the frequency of adaptive responses in combination with head control and the length of such control. The results of Study II showed that the raters found the effects of the new program more positive than those of other intervention conditions and also considered such program a useful complement to formal motor rehabilitation programs.