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Mele M.,University of Calabria | Alo R.,University of Calabria | Avolio E.,University of Calabria | Avolio E.,Health Center srl | And 2 more authors.
Journal of Molecular Neuroscience | Year: 2014

Hypothermia is a physiological condition assuring brain protection against hypoxic-related damages. In this context, investigations carried out on the facultative hibernator Mesocricetus auratus proved to be very useful for establishing the type of neurosignaling role exerted by cerebral α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subtypes during hypoxic/reperfusion injuries of the entrance (EN), torpor (TORP), and arousal (AROU) hibernating states. From the evaluation of the major AMPARs (GluR1 and GluR2), together with their scaffold proteins synapse-associated protein 97 kDa (SAP97) and PICK1, it resulted that GluR1 and SAP97 were mostly upregulated during the hypotensive (EN and TORP) states of the brainstem, amygdala, and hypothalamus, sites which are implicated with cardiovascular, motor, and sleep–wake events. In addition, elevated expression densities of the pro-apoptotic factor Bcl-2-associated X protein (Bax) resulted to be correlated to marked amino–cupric–silver stain signals during both hibernating states. Conversely, an increase of the neuroprotective factor GluR2, together with PICK1 and the anti-apoptotic B cell lymphoma 2 (Bcl-2), appeared to be linked with reduced argyrophilic signals in most of the above areas of the hypertensive AROU state. These first indications highlight distinct protective/degenerative measures of the above factors constituting key on/off switches during the various hibernating states that may provide potential therapeutic bearings on sleeping disorders. © 2014, Springer Science+Business Media New York.


Mele M.,University of Calabria | Avolio E.,University of Calabria | Avolio E.,Health Center srl | Avolio E.,University of California at San Diego | And 4 more authors.
Neuroscience | Year: 2014

Hibernation is a physiological state that by putting vital biological processes at rest enables mammals to protect all organs, especially the brain against ischemic insults and reperfusion injuries. Earlier studies have highlighted the role of hypothalamic (HTH) sites like the periventricular nucleus (Pe) toward sleep-wake and cardiovascular activities of hibernators. In the present work, infusions of Pe with the orexigenic neuropeptide orexin-A (ORX-A) or the novel anti-obesity sympathoinhibitory neuroactive peptide catestatin (CST) have been correlated to differing feeding and motor behaviors in the facultative hibernating hamster Mesocricetus auratus. Behavioral observations showed that treatment with CST provided an anti-obesity activity via the reduction of food intake and body weight for all hibernating states, while ORX-A promoted orexigenic events during mainly the entrance phase. Moreover, hamsters treated with this neuropeptide during the entrance and the arousal hypertensive phases also featured elevated ORX 2 receptor (ORX2R) levels in the third layer of the parietal cortex and lateral HTH (LH), areas involved with feeding, motor plus sleep-wake rhythms. Conversely, ORX-A down-regulated ORX2Rs in the ventromedial (VMH) and supraoptic (SO) HTH nuclei that are associated with anorexigenic effects. Even CST induced mixed ORX2R expression patterns in mostly HTH areas like the evident down-regulation in LH along with the up-regulation in VMH and SO. Overall treatments, especially ORX-A. +. CST led to reduced neurodegenerative phenomena in HTH supporting their importance together with ORX2Rs in preserving hemodynamic activities, feeding and sleep-wake rhythms of this diencephalic station, which may supply useful therapeutic indications for treating cardiovascular disturbances linked with brain dysfunctions. © 2014 IBRO.


Alo R.,University of Calabria | Avolio E.,University of Calabria | Avolio E.,Health Center Srl | Mele M.,University of Calabria | And 4 more authors.
Pharmacology Biochemistry and Behavior | Year: 2014

Several studies have pointed to the amygdala as a main limbic station capable of regulating different stressful states such as anxiety and depression. In this work it was our intention to determine the role of the central amygdala nucleus (CeA) on the execution of either anxiolytic and/or anti-depressant behaviors in the hibernating hamster (Mesocricetus auratus) via infusion of CeA with the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specific for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plus the specific agonist for α4 GABAAR i.e. 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP). Treatment with CNQX appeared to mainly prompt anti-depressant effects as shown by the achievements of swimming feats during forced swim test while THIP prevalently accounted for evident bouts of climbing when exposed to the same test. Moreover, even in the presence of the concomitant administration of both of these compounds, hamsters continued to spend more time in swimming despite this significant behavioral effect resulted to be numerically reduced for hamsters treated with only the α4 GABAAR agonist. Conversely, when these animals were tested in elevated plus maze (EPM), THIP tended to mostly favor anxiolytic activities as exhibited by stressed animals spending more time entering and remaining in EPM open arms. It was interesting to note that behavioral changes induced by both drugs appeared to be also responsible for glutamate receptor (GluR) expression differences as indicated by CNQX favoring an evident up-regulation of GluR2-containing neurons whereas THIP induced an up-regulation, this time of GluR1-containing neurons. Overall, the anti-depressant role of CNQX seems to be mostly attributed to elevated GluR2 levels while an anxiolytic-like effect of THIP was correlated to high GluR1values thereby proposing distinct GluRs as useful therapeutic sites against degenerative diseases such as depression-like behaviors. © 2014 Elsevier Inc.


Avolio E.,University of Calabria | Avolio E.,Health Center srl | Alo R.,University of Calabria | Mele M.,University of Calabria | And 4 more authors.
Behavioural Brain Research | Year: 2012

Recently, environmental stimuli on different neurobiological events, via participation of distinct amygdalar (AMY) ORXergic fibers have aroused wide interests in view of their ability to modify neuronal linked stressful and physiological homeostatic conditions. Results of the present study indicate that ORXergic (ORX-A/B) circuits of the facultative hibernating golden hamster (Mesocricetus auratus) central AMY (CeA) and basolateral AMY (BlA) nuclei constitute major sites of feeding behaviors. Indeed, hamsters after treatment of BlA with ORX-A frequently ingested greater quantities of food as compared to controls, while ORX-B in CeA induced a very (p<0.001) great consumption of water. The same nuclei treated separately with either ORX-A or ORX-B±the selective α1 GABAA benzodiazepine receptor agonist (zolpidem) dedicated less time to eating and drinking sessions. Conversely, hamsters that received the same neuropeptides but this time with the glutamatergic agonist NMDA displayed greater hyperphagic effects above all for ORX-A. When behavioral changes were compared to the expression of the specific ORXergic receptor (ORX-2R), an up-/down-regulating pattern was detected in some limbic areas (AMY, hippocampus and hypothalamus) following treatment with ORX-A or ORX-B plus NMDA. Overall, indications deriving from this study strongly point to hamster BlA-enriched ORX-A fibers in combination with either inhibitory or excitatory signals as main targets of hyperphagic responses while CeA ORX-B activities in presence of these same neuronal signals predominantly induced drinking motivational behaviors. The distinct behavioral activities of these two neuropeptides may have useful clinical bearings toward psychiatric and sleeping disorders such as bulimia and narcolepsy. © 2012 Elsevier B.V.


Alo R.,University of Calabria | Avolio E.,University of Calabria | Avolio E.,Health Center srl | Mele M.,University of Calabria | And 4 more authors.
Molecular Neurobiology | Year: 2016

It is well established that the maintenance of energy expenditure is linked to active hypothalamic neural mechanisms controlling adaptive stimuli such as food intake. Variations of glucose levels and hormonal (leptin plus orexin-A) parameters, which are involved with energy homeostasis during different behavioral states, have not yet been fully defined. In this first study, behavioral analyses of an unpredictable stress model dealing with the actions of a sub-chronic administration of orexin-A (ORX-A) and the anti-hunger neuropeptide, i.e., leptin (LEP) within the hypothalamic suprachiasmatic (SCH) nucleus, were conducted on the valuable hibernating rodent (hamster; Mesocricetus auratus) model noted for its distinct depression and anxiety states. Treatment with LEP accounted for a notable reduction (p < 0.01) of body weight in stressed hamsters that not only executed very evident (p < 0.001) movements to and from elevated plus maze (EPM) but also spent less time in the dark area of the light–dark box test (LDT). Conversely, ORX-A predominantly evoked anxiogenic effects that were inverted by LEP. Interestingly, the anti-hunger neuropeptide accounted for both down-regulated NPY1 transcripts in mostly lateral-posterior hypothalamic areas while up-regulated levels were detected in the parietal cerebral cortex, hippocampus, and amygdala, which largely behaved in an opposite manner to ORX-A-dependent effects. Overall, the present findings corroborate a predominating LEPergic effect of the SCH toward the reduction of hamster anxiety-like behaviors with respect to that of ORX-A signaling, which may constitute useful therapeutic targets for stress-related obesity states. © 2016 Springer Science+Business Media New York


Alo R.,University of Calabria | Mele M.,University of Calabria | Avolio E.,University of Calabria | Avolio E.,Health Center srl | And 2 more authors.
Journal of Molecular Neuroscience | Year: 2014

Studies have pointed to both α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonists and GABAA receptor (GABAAR) agonists as potent antistress agents. In this work, separate subchronic injections of the AMPAR antagonist, 6-ciano-7-nitroquinoxaline-2,3-dione (CNQX), and α1 GABAAR subunit agonist (Zol) within the central amygdala nucleus modified the elevated plus maze performances of hamsters exposed randomly to one of the following stressful conditions: food/water deprivation, forced swimming test, and permanence in cold room. Indeed, stressed hamsters treated with CNQX or Zol displayed a very great (p < 0.001) increase of entrance plus a moderate (p < 0.05) time spent into open arms, respectively. At the cellular level, Zol-treated animals supplied a moderately evident argyrophilic reaction (indicative of neurodegeneration) in the hippocampus while it was absent in the hypothalamus. Interestingly, this reaction was significantly reduced by CNQX supporting its preferential protective role. Furthermore, both agents were responsible for a mixed expression pattern of GluR1 and GluR2 mRNA levels in which Zol overall upregulated GluR1 mRNAs, while they were downregulated by CNQX in the hippocampal oriens-pyramidalis layer and in layer III of the cerebral cortex. These findings support the amygdalar AMPAergic protective response against anxiety states in chronically stressed hamsters, which may constitute useful therapeutic strategies for panic-related mood disorders. © 2014, Springer Science+Business Media New York.

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