Giuseppe Crescimanno

Non-steroidal anti-inflammatory drugs in Parkinson's disease

Parkinsons disease (PD) is known to be a chronic and progressive neurodegenerative disease caused by a selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). A large body of experimental evidence indicates that the factors involved in the pathogenesis of this disease are several, occurring inside and outside the DAergic neuron. Recently, the role of the neuron-glia interaction and the inflammatory process, in particular, has been the object of intense study by the research community. It seems to represent a new therapeutic approach opportunity for this neurological disorder. Indeed, it has been demonstrated that the cyclooxygenase type 2 (COX-2) is up-regulated in SNc DAergic neurons in both PD patients and animal models of PD and, furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) pre-treatment protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6 hydroxydopamine (6-OHDA)-induced nigro-striatal dopamine degeneration. Moreover, recent epidemiological studies have revealed that the risk of developing PD is reduced in humans who make therapeutical use of NSAIDs. Consequently, it is hypothesized that they might delay or prevent the onset of PD. However, whether or not these common drugs may also be of benefit to those individuals who already have Parkinsons disease has not as yet been shown. In this paper, evidence relating to the protective effects of aspirin or other NSAIDs on DAergic neurons in animal models of Parkinsons disease will be discussed. In addition, the pharmacological mechanisms by which these molecules can exert their neuroprotective effects will be reviewed. Finally, epidemiological data exploring the effectiveness of NSAIDs in the prevention of PD and their possible use as adjuvants in the therapy of this neurodegenerative disease will also be examined.

Relationship between the striatal system and amygdaloid paroxysmal activity.

Abstract To study the anatomic pathways through which neostriatal efferent fibers may influence paroxysmal activity focalized in the amygdala, an experiment was carried out both in acute and in chronic cats. Conditioning stimulation of the globus pallidus and substantia nigra greatly reduced the duration of the afterdischarge (AD) or totally blocked the appearance of the seizure, depending on the stimulus parameters. Caudate conditioning stimulation, conducted with the same parameters as nigral or pallidal activation, was less effective in the control of the AD. Chemical lesion of entopeduncular neurons by means of kainic acid injection, resulted in a decrease of about 50% of the inhibition induced by the caudate nucleus on the amygdaloid AD, whereas kainic acid lesion of the substantia nigra resulted in the disappearance of the caudate inhibition. The essential role of the substantia nigra in the final control of amygdaloid paroxysmal activity is thus emphasized.

Temporal structure of the rat's behavior in elevated plus maze test.

Aim of the research was to evaluate, by means of quantitative and multivariate temporal pattern analyses, the behavior of Wistar rat in elevated plus maze (EPM) test. On the basis of an ethogram encompassing 24 behavioral elements, quantitative results showed that 130.14 ± 8.01 behavioral elements occurred in central platform and in closed arms (protected zones), whereas 88.62 ± 6.04 occurred in open arms (unprotected zones). Percent distribution was characterized by a prevalence of sniffing, walking and vertical exploration. Analysis of minute-by-minute duration evidenced a decrease for time spent in open arms and central platform and an increase for time spent in closed arms. As to multivariate t-pattern analysis, 126 different temporal patterns were detected. Behavioral stripes, summarizing distribution of such t-patterns along time, showed that several t-patterns were not homogeneously distributed along the test observational period: t-patterns encompassing behavioral events occurring prevalently in central platform-open arms were observed during the first minutes, whereas t-patterns structured on the basis of events occurring mainly in central platform-closed arms were detected during the last minutes. Therefore, during the observation in elevated plus maze, rats behavior undergoes significant rearrangements of its temporal features. Present research demonstrates, for the first time, the existence of complex and significantly timed behavioral sequences in the activity of Wistar rats tested in elevated plus maze. Application of t-pattern analysis can provide useful tools to characterize the behavioral dynamics of anxiety-related rodent behavior and differentiate the effect of various anxioselective substances.

7-Nitroindazole Protects Striatal Dopaminergic Neurons against MPP+-Induced Degeneration

Abstract:  The neuropathological hallmark of Parkinsons disease (PD) is the selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). In this study, using a microdialysis technique, we investigated whether an inhibitor of neuronal nitric oxide synthase (nNOS), 7‐nitrindazole (7‐NI), could protect against DAergic neuronal damage induced by in vivo infusion of 1‐methyl‐4‐phenylpiridinium iodide (MPP+) in freely moving rats. Experiments were performed over 2 days in three groups of rats: (a) nonlesioned, (b) MPP+‐lesioned, and (c) 7‐NI pretreated MPP+‐lesioned rats. On day 1, control rats were perfused with an artificial CSF, while 1 mM MPP+ was infused into the striatum for 10 min in the other two groups. The infusion of the MPP+ produced a neurotoxic damage of the SNc DA neurons and increased striatal DA levels. On day 2, 1 mM MPP+ was reperfused for 10 min into the striata of each rat group and DA levels were measured as an index of neuronal cell integrity. The limited rise of DA following MPP+ reperfusion in the MPP+‐lesioned rats was due to toxin‐induced neuronal loss and was reversed by pretreatment with 7‐NI (50 mg/kg, intraperitoneally) on day 1, indicating a neuroprotective effect by inhibiting NO formation. These results indicate that neuronally derived NO partially mediates MPP+‐induced neurotoxicity. The similarity between the MPP+ model and PD suggests that NO may play a significant role in its etiology.

Structure of rat behavior in hole-board: I) multivariate analysis of response to anxiety.

Aim of present paper was to carry out an analysis of rat behavior in hole-board following different multivariate approaches. Thirty male Wistar rats were observed in a hole-board apparatus and their behavior recorded for 10 min through a digital videocamera for a following frame-by-frame analysis. Both descriptive and multivariate analyses were used. Descriptive analysis showed that roughly 85% of the whole behavioral structure encompassed six patterns appearing during the first minute of observation: walking, climbing, rearing, immobile-sniffing, edge-sniff and head-dip. As to multivariate approach, cluster analysis showed three main dyadic associations: [edge-sniff/head-dip], [walking/climbing], [face-grooming/body-grooming]. Path diagram, obtained on the basis of relative frequencies of transitions among behavioral patterns (stochastic analysis), emphasized cluster analysis results. Adjusted residuals confirmed, from a statistical point of view, the strong relationships among specific patterns. Results demonstrate that immobile-sniffing has a crucial role in rat behavioral organization and head-dip is closely related with edge-sniff which is suggested to be a specific sniffing activity of holes edge never properly considered. Present research shows that multivariate approaches, revealing patterning among different behavioral elements in hole-board, could improve test reliability, providing a more useful tool to investigate behavioral effects of anxiolytic drugs.

T-pattern analysis for the study of temporal structure of animal and human behavior: A comprehensive review

A basic tenet in the realm of modern behavioral sciences is that behavior consists of patterns in time. For this reason, investigations of behavior deal with sequences that are not easily perceivable by the unaided observer. This problem calls for improved means of detection, data handling and analysis. This review focuses on the analysis of the temporal structure of behavior carried out by means of a multivariate approach known as T-pattern analysis. Using this technique, recurring sequences of behavioral events, usually hard to detect, can be unveiled and carefully described. T-pattern analysis has been successfully applied in the study of various aspects of human or animal behavior such as behavioral modifications in neuro-psychiatric diseases, route-tracing stereotypy in mice, interaction between human subjects and animal or artificial agents, hormonal-behavioral interactions, patterns of behavior associated with emesis and, in our laboratories, exploration and anxiety-related behaviors in rodents. After describing the theory and concepts of T-pattern analysis, this review will focus on the application of the analysis to the study of the temporal characteristics of behavior in different species from rodents to human beings. This work could represent a useful background for researchers who intend to employ such a refined multivariate approach to the study of behavior.

Multivariate data handling in the study of rat behavior: an integrated approach.

The aim of the present article is to provide a methodological description of various approaches to multivariate data handling in the study of rodent behavior. To this purpose, 42 male Wistar rats were tested in an open field, and their behavior was recorded through a digital video camera for a subsequent analysis by means of a software coder. After a preliminary evaluation of descriptive features such as durations and percent distributions, we carried out different kinds of multivariate approaches represented by stochastic, cluster, adjusted residual, and T-pattern analyses. In the attempt to depict behavior in a straightforward way, the results of each analysis were graphically illustrated through path diagrams, dendrograms, histograms, and tree-shaped T-patterns. Path diagrams showed a clear behavioral convergence toward immobile sniffing; dendrograms highlighted three different dyadic clusters: walking/climbing, immobile-sniffing/immobility, and paw-licking/grooming; adjusted residuals confirmed, for the same patterns, highly significant association values; finally, T-pattern analysis showed a highly recurring temporal sequence of events encompassing walking, climbing, immobile sniffing, and immobility. Such results, drawing attention to specific behavioral patternings, strengthen and extend previous findings on rodent behavior. We suggest that T-pattern analysis, integrated with other multivariate approaches, can provide a more detailed and complete rat behavior representation, very different from classical quantitative

The Unilateral Nigral Lesion Induces Dramatic Bilateral Modification on Rat Brain Monoamine Neurochemistry

6‐Hydroxydopamine (6‐OHDA) is a neurotoxic compound commonly used to induce dopamine (DA) depletion in the nigrostriatal system, mimicking Parkinsons disease (PD) in animals. The aim of the present study was to evaluate the 7‐day effect of unilateral nigral lesion on rat brain monoamine neurochemistry. Five brain regions were examined: the brain stem, cerebellum, hippocampus, striatum, and cortex. 6‐OHDA‐unilateral lesion dramatically modified DA, serotonin (5‐HT) and their metabolites contents in both sides of the different brain nuclei. Furthermore, unilateral 6‐OHDA lesion reduced DA and 5‐HT contents and produced a robust inversion of their turnover in the nonlesioned side compared to sham‐operated rats. These data suggest that 6‐OHDA unilateral nigral lesion produces bilateral monoamine level modifications, and this piece of evidence should be taken into account when one interprets data from animal models of unilateral PD.

The role of the claustrum in the bilateral control of frontal oculomotor neurons in the cat.

SummaryThe effect of claustrum (CL) stimulation on the spontaneous unitary activity of ipsi and contralateral frontal oculomotor neurons, was studied in chloralose-anaesthetized cats. A total of 205 units was bilaterally recorded in the medial oculomotor area, homologous of the primate “frontal eye fields” 127 neurons were identified as projecting to the superior colliculus; for 33 of these last units stimulation of the ipsilateral CL provoked an excitatory effect lasting 10–25 ms and appearing with a latency of 5–15 ms; on 8 units the excitatory effect was followed by an inhibition lasting 100–250 ms. Ninety-eight of the 127 neurons were also tested through activation of the contralateral CL: 13 cells showed an excitatory effect lasting 10–35 ms and appearing with a latency of 20–50 ms. In three of the thirteen units the excitatory effect was followed by an inhibition lasting 100–150 ms. Complete section of the corpus callosum abolished the contralateral CL effect, suggesting the existence of a direct claustro-contralateral oculomotor cortex pathway running through the corpus callosum. The results could support the hypothesis that the CL may play a role in the bilateral control of the visuomotor performance.

Temporal patterns analysis of rat behavior in hole-board.

The aim of present research was to analyze the temporal structure of rodents anxiety-related behavior in hole-board apparatus (HB). Fifteen male Wistar rats were tested for 10 min. Video files, collected for each subject, were coded by means of a software coder and event log files generated for each subject. To assess temporal relationships among behavioral events, log files were processed by means of a t-pattern analysis. 14 two-element t-patterns, four t-patterns encompassing 3 events and 2 t-patterns encompassing 4 and 5 events respectively were revealed. It was demonstrated that rat behavior in HB was mainly structured on the basis of the temporal patterning among exploratory events; these ones were the most structured t-patterns detected and appeared mainly during the first 5 min of exploration, while grooming t-patterns were present prevalently after the fifth minute. Specific t-pattern parameters, such as overall occurrences and mean duration of each given t-pattern in each subject, were also studied. Present research: (a) reports for the first time that some behavioral events occur sequentially and with significant constraints on the interval lengths separating them; (b) presents the temporal flows of some behavioral elements through multimodal behavioral vectors; (c) could also be used to improve HB test reliability and its ability to detect even small induced behavioral changes.