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NEUROPHARMACOLOGY
Comparative Neuroanatomy Laboratory, Ecology Department, University of Calabria, Ponte Pietro Bucci, Cosenza, Italy (M.C., M.M., R.A., G.G., T.G., An.C., R.M.F.); and Faculty of Medicin, La Sapienza University of Rome, Rome, Italy (Al.C.)
Received April 22, 2005; accepted June 15, 2005.
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Abstract |
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; Sakata et al., 1997; Parmentier et al., 2002). The histaminergic neuronal fibers, originating from the hypothalamus, are projected extensively in the brain and promote their actions via three pharmacologically distinct receptor subtypes denoted as HnR (H1–3R) (Leurs et al., 2005). The results of this and other studies have established that all subtypes display a postsynaptic location, with the exception of H3R, which has instead shown to be located at both presynaptical and postsynaptical sites. A distribution pattern that appears to be tightly correlated to some of the above homeostatic mechanisms, namely eating behaviors and thermoregulation, which are typically controlled by the different subtypes of the hypothalamic nuclei (Haas and Panula, 2003). Moreover, broad effects of H3R blockade with selective and more potent inverse agonists have recently linked the activities of this subtype to the impairment of aging parameters, disturbances of cognition functions along with sensorimotor deficits that are considered to be the more common deleterious features of central nervous system disorders such as Alzheimer's disease (AD) and schizophrenia (Fox et al., 2005).
Accumulating data dealing with neurodegenerative disorders have suggested the neurotoxicant 3-nitropropionic acid (3-NP), a plant (freckled milk vetch)-derived blocker of mitochondrial respiration, to be a valuable chemical agent for the establishment of biomolecular events in such disorders (Bizat et al., 2003). 3-NP, which manages to enter in humans by accidental ingestion of contaminated mildewed sugar cane (Deshpande et al., 1997), is capable of inducing necrotic and apoptotic events in some cerebral regions. Thus, it mimicks salient motor and neuropathological features that typically resemble those reported for patients suffering from neuropathologies such as Huntington's disease (Fernagut et al., 2002), AD, and cerebral ischemia (Pang and Geddes, 1997).
Recently, 3-NP has been used in ischemic preconditioning paradigms (Brambrink et al., 2004) from which have been defined adaptable neuroprotective mechanisms that are induced in oxygen-deprived activities of AD (Higuchi et al., 2000) as well as in animals during hibernation (Stenzel-Poore et al., 2003). On the basis of these results, it seemed interesting to propose the effects of the freckled milk vetch-derived neurotoxin in a highly appropriate hibernating model, the Syrian golden hamster. This rodent is a permissive hibernator that undergoes profound neurophysiological modifications, following particular environmental conditions such as hypothermia, which allow the animal to survive through these extraordinary conditions (Ueda and Ibuka, 1995). As a matter of fact, it is throughout the different hibernating stages in rodents, i.e., during enter, torpor, and arousal states, that brain vascular homeostasis plus the reprogramming of gene expression (Epperson and Martin, 2002) are strongly influenced by neuronal mediators such as the histaminergic system (Panula et al., 2000). In this context, it was the intention of the present study to investigate 3-NP-dependent neurodegenerative effects on the transcriptional activity of the two main histaminergic subtypes (H1,3R) plus neuronal ultrastructural changes in key brain areas of the sensory and incentive motivational circuit (Balleine et al., 2003) such as the cortical layers and amygdala. These effects were compared with the major motor controlling brain center (striatum) to identify not only the specific subtype but also the brain site(s) that may be linked with neuroprotective processes adopted by this hibernating rodent model.
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Materials and Methods |
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) was used to assess severity rating by a three-level scale of the following five items in the symptomatic rat (up to 100 mg/kg) and hamster (up to 200 mg/kg) and asymptomatic animals. A value ranging from 0 to 2 was assigned to each type of behavior for a maximal score of 10 for all behaviors that constitute the main motor symptoms: hind limb clasping, reduced global activity in a freely moving environment, hind limb dystonia, truncal dystonia, and balance adjustments to a postural challenge. Due to the extreme vulnerability effects of chronic 3-NP doses in rats, the role of histamine blockers was carried out on only acute-treated animals. For this part, both rats and hamsters received, 1 h before 3-NP treatment, a single dose (i.p.) of the H3R antagonist thioperamide (10 mg/kg body weight), whereas other animals received a combined dose containing H1R antagonist pyrilamine (20 mg/kg body weight) and H2R antagonist cimetidine (200 mg/kg body weight), a combination that is capable of successfully regulating neuronal transcriptional activities (Patkai et al., 2001).
For ultrastructural and H1,3R transcription studies, the brain of both rodents was rapidly removed 12 h after treatment for all groups and stored, in the case of the latter study, at –40°C for further analyses. Animal maintenance and all experimental procedures were carried out in accordance with the Guide for Care and Use of Laboratory Animals issued by the European Communities Council Directive (1986) (86/609/EEC). Efforts were made to minimize animal suffering and reduce the number of specimens used.
Ultrastructure. The ultrastructure of neurons in some encephalic regions of all animal models was carried out in perfusion-fixed (4% glutaraldehyde) brains. Amygdalar, striatal, and cortical regions of both rodents were carefully dissected out using the coordinates that are reported in the rat (Paxinos and Watson, 1982) and hamster (Morin and Wood, 2001) brain atlases; after, dehydrated blocks of tissue were embedded in Epon 812, and the ultrathin sections were examined using the Zeiss EM 900 transmission electron microscope (Carl Zeiss GmbH, Jena, Germany).
To estimate the neuromorphological effects of 3-NP, quantitative analysis was carried out on some major motor and motivational controlling brain areas such as striatum and amygdala of hamsters treated with an acute dose of this neurotoxin and compared with that of rats. For this part, semithin sections that were obtained from the above isolated telencephalic regions were counterstained with toluidine blue, and total numbers of damaged and normal neurons were assessed with a 40x objective with a Vidas Image Analyzer (Carl Zeiss GmbH) using a 6.5 x 6.5 grid composed of 42 test points and 21 test lines. Neurons with round nuclei, visible nucleoli, and clear cytoplasma lying within the grid were considered undamaged, whereas neurons with shrunken nuclei and vacuolated dark cytoplasma (dark cells) were considered damaged. Because many degenerating profiles were included in such counts and given that the pathological processes may alter the normal ultrastructural features of neurons and nonneuronal cells, the identification of degenerating elements belonging to one or another cell type is necessarily tentative and based purely on comparisons with normal cells (Kuljis et al., 1997).
Amino Cupric Silver Stain. The identification of neuron degeneration due to 3-NP treatment was handled according to the precipitation of ionic silver staining methods (De Olmos et al., 1994). Briefly, for this part, brain sections (30 µm) of animals exposed to the freckled milk vetch neurotoxin were initially preimpregnated with a series of nitrates (such as silver and others), subsequently impregnated with silver nitrate, lithium, and ammonium hydroxides, and stained with neutral red (Thermo Electron Corporation, Milan, Italy). The chemical-dependent subcellular damages were observed and evaluated with a bright-field Dialux EB 20 microscope (Leitz, Wetzlar, Germany).
H1,3R Transcription Activity. The sequence of H1,3R, determined from total RNA of 3-NP-treated whole brains of both rodents, was prepared with TRI reagent (Sigma-Aldrich, St. Louis, MO) and finally dissolved in diethyl pyrocarbonate-water (Sigma-Aldrich). Reverse transcription reaction was performed using 2 µg of total RNA with RETROscript kit (Celbio, Milan, Italy) at 44°C for 1 h after template denaturation at 75°C for 3 min. Amplification of H1R and H3R was performed using EuroTaq Polymerase (Celbio) with gene-specific primer sets.
Synthetic oligonucleotide probes (Roche Applied Science, Indianapolis, IN) were designed from sequencing of the above PCR products. The antisense probes were complementary to encoding sequence bp 850 to 894 and bp 829 to 870 of the mature protein, respectively, for H1R and H3R. To perform in situ hybridization on 3-NP-treated rat and hamster brains, antisense and sense probes were labeled by 3'-tailing with digoxigenin-11-dUTP according to the DIG oligonucleotide tailing kit provided by Roche Applied Science. The reaction was incubated at 37°C for 30 min and then stopped with 0.2 M EDTA, pH 8.0. Probe concentration was determined by quantification against known standards on Hybond N+ filters (Amersham Biosciences Inc., Piscataway, NJ). Briefly, brains sections (10 µm) mounted on polylysine-coated slides (Thermo Electron Corporation) were stored at –40°C; subsequently, 100 ng of antisense probe in 100 µl of hybridization solution was added for each section before overnight in situ hybridization at 50°C in a humidified chamber according to Kia et al. (2002). Nonspecific hybridization was obtained on slides incubated with the sense probe. For immunological detection, sections were coverslipped for 45 min with phosphate-buffered saline containing 2% normal sheep serum (Sigma-Aldrich) and 0.3% Triton X-100 (Sigma-Aldrich); subsequently, 1:100 anti-digoxigenin alkaline phosphatase antibody (Roche Applied Science) was added for 2 h at room temperature, and the alkaline phosphatase color reaction buffer (nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate) was added to sections and incubated for 72 h in a humidified dark chamber. The neuronal hybridization signals were observed at a bright-field Dialux EB 20 microscope (Leitz) under a phase-contrast objective (x40), and transcriptional activity was evaluated with a Panasonic Telecamera (Canon Objective Lens FD, 50 mm, 1:3.5) attached to a Macintosh computer-assisted image analyzer system running an Image software of the National Institutes of Health. The data, expressed as the mean ± S.E.M., were evaluated by one-way analysis of variance followed, where necessary, by Student's t test.
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). A first major behavioral result consisted of less vulnerable effects produced by this freckled milk vetch neurotoxin in the hibernating rodent, even for those doses (100 mg/kg; 50 mg/ml) that in the rat are considered to be very lethal as shown by the immediate overt motor symptoms such as hind limb and truncal dystonia, hind limb clasping, and reduced global activity (Fig. 1).
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Effects of 3-NP on H1,3R Transcription Activity. With the aim of evaluating whether these degenerative processes included damages of the histaminergic signaling system, the expression levels and sequence pattern of the major HnR subtypes (H1/3R) were determined in some brain regions of the hamster and rat. From the reverse transcriptase-PCR investigations, it was possible to observe a high degree of nucleotide homology (>85%) for the two subtypes in both rodents (Fig. 3a). This homology was further confirmed by the very similar amino acid sequence of H3R with the exception of some substitutions and, in particular, isoleucine and leucine being replaced by lysine and asparagine at positions 225 and 233, respectively, of the third intracellular loop in the hamster.
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The absence of any type of transcriptional variations in the hamster could very well be attributed to the asymptomatic state that characterized this hibernating rodent model with respect to the symptomatic state of the rat. As a matter of fact, when the hamster received an acute dose, which was responsible for no abnormal motor behaviors with respect to a dose (200 mg/kg) capable of promoting symptomatic conditions, a marked down-regulation of H1R neurons was obtained in a comparable manner with COR V of the symptomatic rat (Fig. 4a). A somewhat similar condition was detected not only in this cortical layer but also in the lateral amygdala nucleus (Lat) and central amygdala nucleus (Ce) (>40%, p < 0.05) (Fig. 4c) of the hamster. Conversely, a very evident (>80%, p < 0.001) up-regulation of H3R neurons in COR III (Fig. 4b), and the majority of the amygdalar areas (Fig. 4d) appeared to be also linked to the symptomatic conditions of the hamster. This substantial up-regulating trend for H3R neurons in COR V (Fig. 5a) and above all in Ce, Lat, and basolateral amygdala nucleus (Fig. 5c) was conserved (>130%, p < 0.001) even after a chronic treatment that accounted for exaggerated motor abnormalities such as truncal and hind limb dystonia, despite a nonsignificant up-regulating activity of H1R neurons resulting in only the corticomedial amygdala nucleus (Fig. 5d) with respect to the marked low levels in most rat brain areas such as COR III (Fig. 5b).
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).
At the structural level, the different 3-NP doses proved to be responsible for evident structural damages that were easily observed with the light microscope using amino cupric silver staining methods. This method has proven to be a helpful tool for the detection of degenerative processes in neuronal cell bodies, dendrites, and axons as well as the surveying of cell damage in primary sites of trauma (De Olmos et al., 1994). It was, however, at the ultrastructural level that substantial neurodegenerative processes induced by the different doses of 3-NP were shown to occur in a more selective manner. As a matter of fact, greater structural alterations consisting of an increased number of neurons that displayed an evident dark nucleus plus crenated cell membrane and phenomena of vacuolation appeared to prevalently characterize the different brain regions such as the striatum and cortex of the rat, which is in line with the very early acute damages involving membrane thickness and dilated cisternal formations in the former brain area of this same animal under the influence of the freckled milk vetch-derived neurotoxin (Seaman and Phelix, 2005). Conversely, a low number of unimpaired mitochondrial crests were instead reported for hamster brain areas such as the amygdala with respect to the greater number reported for the rat and other rodent brain areas for that matter (La Fontaine et al., 2000). The fewer structural alterations in this telencephalic region of hamster is supported by the low number of damaged dendrites detected in this same brain region of animals exposed to other degenerative-dependent events like stress (Vyas et al., 2002). A feature that appears to be accompanied by an abundance of neuronal elements, probably of the A-potassium current type (Graß et al., 2004). These elements may serve as a buffer system for the excess production of traumatic neuronal products and at the same time play a major role for the consequential synaptogenetic plasticity responses not only for ischemic insults (Arendt, 2004) but also against 3-NP-induced abnormal motor behaviors.
Recently, the demonstration of 3-NP effects accounting for neurotransmission dysfunctions (Saulle et al., 2004) tends to suggest the importance of certain neuromediating systems, such as the histaminergic fibers in the neurodegenerative processes of hibernating animals (Epperson and Martin, 2002). A relationship that appears to be very tightly linked to the distinct expression pattern of H1,3R subtypes in both rodents as suggested by recent results showing diminished and increased mRNA levels of the two subtypes, respectively, in cortical plus other brain regions such as the hypothalamus and hippocampus of the hibernating hamster with respect to nonhibernating and the rat for that matter (M. Madeo, T. Granata, R. M. Facciolo, A. Carelli, S. Tripepi, and M. Canonaco, unpublished data). It is noteworthy that the low expressing levels of this subtype in the major motor centers such as the striatum and cortex of the hamster treated with 3-NP seem to fit very nicely with the low levels of H1RinAD patients (Higuchi et al., 2000) and accelerated kindling seizures (Chen et al., 2003). On the other hand, high expression levels of H3R, especially in amygdalar areas as well as the cortex layers of the hamster treated with 3-NP, appear to be consistent with species-specific responses as shown by an up-regulation of this subtype in striatum of stressed rats (Ito et al., 1999) as compared with a down-regulation in diencephalic areas of other pathological states such as status epilepticus in the rat (Jin et al., 2005). Moreover, even environmental-related stressful conditions tend to play a determinant role on the transcriptional activity of this subtype as confirmed by the varying photoperiodic effects accounting for a down-regulating trend of H3R mRNA levels in the same brain region of another species, the Siberian hamster (Barrett et al., 2005).
Indeed, the high expressing activity of H3R neurons in the Syrian golden hamster, which is comparable with the same levels detected during the stressful moments of hibernation, i.e., blocking of the arousal phase probably through the inhibition of hippocampal activity (Sallmen et al., 2003), appears to be in good agreement with the motor difficulties displayed by Parkinson's disease patients displaying similar subtype levels (Anichtchik et al., 2001). Interestingly, the inhibition of H3R influences on 3-NP-dependent abnormal motor behaviors via its antagonist, thioperamide (M. Madeo, G. Giusi, R. Alò, T. Granata, E. Perrotta, R. M. Facciolo, A. Carelli, M. Canonaco, personal communication), plus the concomitant induction of elevated H1R mRNA-expressing neurons, tend to further emphasize the potential neuroprotective role of this latter subtype against freckled milk vetch-derived neurotoxin effects. Hence, it is not surprising that the specific H3R antagonist is capable of reducing brain lesions in interleukin-9-activation of cerebral palsy (Patkai et al., 2001). Conversely, H1R/H2R antagonists are more inclined to accelerate ischemic brain damages (Otsuka et al., 2003), a condition that appears to be tightly correlated to the low expression levels of H1R that are instead typical of cortical areas of nonmotivated motor syndromes as in the case of depressed patients (Kano et al., 2004).
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), may turn out to be key protective components for the different brain regions of patients with neurodegenerative disorders. |
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ABBREVIATIONS: HnR, histamine receptor subtypes; AD, Alzheimer's disease; 3-NP, 3-nitropropionic acid; PCR, polymerase chain reaction; COR, cortex; Lat, lateral amygdala nucleus; Ce, central amygdala nucleus.
Address correspondence to: Marcello Canonaco, Comparative Neuroanatomy Laboratory, Ecology Department, University of Calabria, Ponte P. Bucci, 87030 Arcavacata di Rende, Cosenza, Italy. E-mail: canonaco{at}unical.it
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R (a and b) or H3R (c and d) antagonists with respect to symptomatic without antagonists and compared with their corresponding controls (vertical and horizontal line, respectively) as described under Materials and Methods. *, p < 0.05; **, p < 0.01; ***, p < 0.001. For abbreviations, check