Hesperidin protects against behavioral alterations and loss of dopaminergic neurons in 6-OHDA-lesioned mice: the role of mitochondrial dysfunction and apoptosis.

Hesperidin is a flavonoid glycoside that is frequently found in citrus fruits. Our group have demonstrated that hesperidin has neuroprotective effect in 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD), mainly by antioxidant mechanisms. Although the pathophysiology of PD remains uncertain, a large body of evidence has demonstrated that mitochondrial dysfunction and apoptosis play a critical role in dopaminergic nigrostriatal degeneration. However, the ability of hesperidin in modulating these mechanisms has not yet been investigated. In the present study, we examined the potential of a 28-day hesperidin treatment (50 mg/kg/day, p.o.) in preventing behavioral alterations induced by 6-OHDA injection via regulating mitochondrial dysfunction, apoptosis and dopaminergic neurons in the substantia nigra pars compacta (SNpc) in C57BL/6 mice. Our results demonstrated that hesperidin treatment improved motor, olfactory and spatial memory impairments elicited by 6-OHDA injection. Moreover, hesperidin treatment attenuated the loss of dopaminergic neurons (TH+ cells) in the SNpc and the depletion of dopamine (DA) and its metabolities 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of 6-OHDA-lesioned mice. Hesperidin also protected against the inhibition of mitochondrial respiratory chain complex-I, -IV and V, the decrease of Na + -K + -ATPase activity and the increase of caspase-3 and -9 activity in the striatum. Taken together, our findings indicate that hesperidin mitigates the degeneration of dopaminergic neurons in the SNpc by preventing mitochondrial dysfunction and modulating apoptotic pathways in the striatum of 6-OHDA-treated mice, thus improving behavioral alterations. These results provide new insights on neuroprotective mechanisms of hesperidin in a relevant preclinical model of PD.

Hesperidin Ameliorates Anxiety-Depressive-Like Behavior in 6-OHDA Model of Parkinson's Disease by Regulating Striatal Cytokine and Neurotrophic Factors Levels and Dopaminergic Innervation Loss in the Striatum of Mice.

The mechanisms underlying the neuroprotective effects of hesperidin in a murine model of PD are not fully elucidated. The current study was carried out to investigate the ability of hesperidin in modulating proinflammatory cytokines, neurotrophic factors, and neuronal recovery in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic neuronal loss. Adult male C57BL/6 mice were randomly assigned into four groups: (I) sham/vehicle, (II) sham/hesperidin, (III) 6-OHDA/vehicle, and (IV) 6-OHDA/hesperidin. Mice received a unilateral intrastriatal injection of 6-OHDA and treated with hesperidin (50 mg/kg; per oral) for 28 days. After hesperidin treatment, mice were submitted to behavioral tests and had the striatum removed for neurochemical assays. Our results demonstrated that oral treatment with hesperidin ameliorated the anxiety-related and depressive-like behaviors in 6-OHDA-lesioned mice (p < 0.05). It also attenuated the striatal levels of proinflammatory cytokines tumor necrosis factor-α, interferon-gamma, interleukin-1ß, interleukin-2, and interleukin-6 and increased the levels of neurotrophic factors, including neurotrophin-3, brain-derived neurotrophic factor, and nerve growth factor in the striatum of 6-OHDA mice (p < 0.05). Hesperidin treatment was also capable to increase striatal levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid and protects against the impairment of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (p < 0.05). In conclusion, this study indicated that hesperidin exerts anxiolytic-like and antidepressant-like effect against 6-OHDA-induced neurotoxicity through the modulation of cytokine production, neurotrophic factors levels, and dopaminergic innervation in the striatum.

Asymmetric post-natal development of superior cervical ganglion of paca (Agouti paca).

Functional asymmetry has been reported in sympathetic ganglia. Although there are few studies reporting on body side-related morphoquantitative changes in sympathetic ganglion neurons, none of them have used design-based stereological methods to address this issue during post-natal development. We therefore aimed at detecting possible asymmetry-related effects on the quantitative structure of the superior cervical ganglion (SCG) from pacas during ageing, using very precise design-based stereological methods. Forty (twenty left and twenty right) SCG from twenty male pacas were studied at four different ages, i.e. newborn, young, adult and aged animals. By using design-based stereological methods the total volume of ganglion and the total number of mononucleate and binucleate neurons were estimated. Furthermore, the mean perikaryal volume of mononucleate and binucleate neurons was estimated, using the vertical nucleator. The main findings of this study were: (1) the right SCG from aged pacas has more mononucleate and binucleate neurons than the left SCG in all other combinations of body side and animal age, showing the effect of the interaction between asymmetry (right side) and animal age, and (2) right SCG neurons (mono and binucleate) are bigger than the left SCG neurons (mono and binucleate), irrespective of the animal age. This shows, therefore, the exclusive effect of asymmetry (right side). At the time of writing there is still no conclusive explanation for some SCG quantitative changes exclusively assigned to asymmetry (right side) and those assigned to the interaction between asymmetry (right side) and senescence in pacas. We therefore suggest that forthcoming studies should focus on the functional consequences of SCG structural asymmetry during post-natal development. Another interesting investigation would be to examine the interaction between ganglia and their innervation targets using anterograde and retrograde neurotracers. Would differences in the size of target organs explain ganglia structural asymmetry?

Behavioral and stereological analysis of the prefrontal cortex of rats submitted to chronic alcohol intake.

Alcohol consumption has been identified as a causal factor promoting changes in different molecular and cellular mechanisms resulting in neurodegeneration. This process is specific to certain brain regions and its effects on different areas of the brain can result in a variety of deleterious consequences. The prefrontal cortex (PFC) appears to be particularly sensitive to alcohol-induced neurodegeneration; this region is quite complex, as it is responsible for high order mental processes such as decision making. Thus, it is important to have precise and unbiased data of neuronal morphology parameters to understand the real effects of alcohol on the PFC. This study aimed to investigate alcohol-induced neurodegeneration in the PFC by utilizing behavioral and stereological methods. In the first phase of the study, we utilized eighteen animals, six controls and twelve alcohol-treated, that were submitted to voluntary chronic alcohol ingestion for four or eight weeks. Their brains were analyzed by design-based stereology methods to assess number and volume parameters regarding neuronal integrity in regions of the PFC (prelimbic - PL, infralimbic - IL and anterior cingulate - ACC). In the second phase of the study, six animals were utilized as controls and eight animals were submitted to the same alcohol ingestion protocol and to a behavioral decision-making test. In conclusion, our findings indicate that chronic alcohol consumption promotes a decrease in volume in the prelimbic and in the anterior cingulate, a decrease of mean neuronal volume in the anterior cingulate cortex and a decrease of total volume of neurons in the IL area. We did not observe changes in decision-making behavior in either of the two periods of alcohol intake. This shows that morphological changes occur in specific regions of the prefrontal cortex, a noble area of cognitive functions, induced by chronic alcohol consumption.

Áreas cerebrais do macaco prego (Cebus apella Linnaeus, 1766) / Brain areas of capuchin monkeys (Cebus apella Linnaeus, 1766)

O Cebus apella é uma espécie protegida por lei, contribui para a manutenção dos ecossistemas florestais com comportamento social semelhante aos humanos. Descrevemos a topografia das áreas cerebrais do Cebus apella, para observar e descrever a organização dos sulcos e lobos em cada hemisfério cerebral, esquematizando-os. A análise foi feita pela observação de 30 (trinta) hemisférios cerebrais, fixados em álcool 70 %, dissecados sob mesoscopia de luz. Foram descritos 4 (quatro) lobos cerebrais principais: Frontal; Parietal; Temporal e Occipital e suas complexas circunvoluções cerebrais, característica de primatas com movimentos rápidos. A análise foi: vista medial apresentando sulco caloso marginal, parieto-occipital, calcarino, para-calcarino, retro-calcarino, colateral, occipito-temporal e rostral; vista lateral apresentando sulco rectus, frontal médio, ramo horizontal arcuatus, superior subcentral, arcuatus, lateral, paralelo, temporal inferior, central, intraparietal, angular, pré-occipital transverso, occipital tranverso ou lunatus, occipital inferior, occipital médio, occipital superior e parieto-occipital. São constantes na vista lateral os sulcos lateral, paralelo, central, intraparietal e lunatus, os demais variam de um antímero para o outro. Na vista medial os sulcos parieto-occipital, caloso marginal e calcarino são constantes. Na morfologia dos giros cerebrais a presença ou ausência dos sulcos e suas variações são indicativos de uso maior ou menor de córtex cerebral, característica importante para o domínio das circunstâncias sociais e ambientais, para garantir a sobrevivência da espécie.

The Cebus is a species protected by law, which contributes to the maintenance of forest ecosystems, presenting a social behavior similar to humans. The brain area topography of Cebus is described in this paper, with the purpose of observing and describing the organization of the sulcus and lobes in each cerebral hemisphere, outlining them. The analysis was performed by observing thirty (30) cerebral hemispheres fixed in 70% alcohol, dissected under mesoscopy light. Four (4) major cerebral lobes have been described: Frontal; Parietal; Temporal and Occipital and their complex brain convolutions, characteristic of primates with rapid movements. The areas analyzed were: facies medialis showing marginal sulcus callosum, parietal-occipital, calcarinus, retro calcarinus, collaterales, occipital temporales and rostralis; facies lateralis showing sulcus rectus, medialis rostralis, horizontal arcuatus segment, superior sub-central, arcuatus, lateralis, parallel, inferior temporalis, centralis, intraparietalis, angular, transverse pre-occipital, tranverse occipital or lunatus, inferior occipital, medius occipital, superior occipital and parietalis occipital. The lateral view presented the lateral, parallel, central, intraparietal and lunatus sulcus, and the other ranged from one antimere to the other. The medialis view presented the parietal-occipital sulcus, marginal and calcarinus callosum. The morphology of the brain gyrus, the presence or absence of sulcus and their variations are an indication of greater or lower use of the brain cortex, an important characteristic for the domain of the social and environmental circumstances to guarantee the survival of the species.