Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of <b><i>Garcinia</i></b> Biflavonoid Complex

Abstract

Background: Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression. Purpose: This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc). Methods: Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN₃) (15 mg/kgBw/day) and aluminium chloride (AlCl₃) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN₃; E received AlCl₃; F received NaN₃ then GBc subsequently; G received AlCl₃ then GBc subsequently; H received NaN₃ and GBc simultaneously while I received AlCl₃ and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays. Results: Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl₃ and NaN₃. These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis. Conclusion: Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl₃ and NaN₃-induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.

Inhibitory potentials of Cymbopogon citratus oil against aluminium-induced behavioral deficits and neuropathology in rats

“…Our findings showed that treatment with Al evidently increases oxidative stress and brain injury as there was significant repression in the levels of SOD, GPx, and CAT in the cerebellar homogenate relative to control. These results corroborated previous findings that Al treatment results to downregulation of antioxidant enzymes, causing an imbalance between pro-oxidant and antioxidant potentials [5,26]. On the contrary, the administration of ESO before and after Al treatment showed a reversal of the deleterious effects on oxidative redox within the cerebellum of rats.…”

“…The mechanism of cytotoxic and/or neurotoxic substances are thought to be mainly due to the oxidative stress involved in the production of reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, superoxide radical and hydroxyl radical. Moreover, the degree of oxidative damage is depended on the balance between the oxidative stress and the efficiency of the endogenous antioxidant system that is found in the majority of cells [5]. Generally, brain tissues are highly susceptible to attacks from free radicals due to highly unsaturated lipid contents [28].…”

“…This observation was further buttressed by results from SOD, CAT, and GPx analyses. Recent evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger-SOD as a common player in the pathogenic cascades of many neurodegenerative pathologies like AD [5]. Similarly, GPx an enzyme that reduces lipid hydroperoxides to their corresponding alcohols and reduces free hydrogen peroxide to water, and CAT, which protects SOD by converting H 2 O 2 to water and oxygen, have both been implicated in AD etiology.…”

“…Most studies on AD focus on the cerebral cortex and hippocampus with undoubtedly established associated roles in learning, memory, and behavioral functions, consequently causing researchers to pay less attention to the cerebellum and other areas of the brain during the clinical onset as well as the progression of AD pathology. Despite the emergence of investigative studies on the cerebellum in AD pathology suggesting that degenerative changes within the cerebellum may be inclusive in both pathogenesis and symptomatic manifestation of AD, there is still a paucity of comprehensive scientific evidence to substantiate the neuropathological observations occurring in the cerebellum of AD subjects [4,5]. Such scientific evidence is imperative for isolating potential therapeutic agents against neuronal loss in AD and preventing resulting behavioral deficits.…”

Corticohippocampal Neuroenergetics and histomorphology in aluminium-induced neurotoxicity: Putative therapeutic roles of ascorbic acid and nicotine

“…In line with findings from this study, aluminium has been reported to induce anxiety and memory decline (Crépeaux et al, 2017;Morris et al, 2017;Olajide et al, 2018). The anxiogenic propensity of aluminium can be attributed to the role it plays in mediating neurochemical disturbances and perturbation of neurotransmission in the brain (Caito and Aschner, 2015;Maya et al, 2016;Olajide et al, 2017a;Yokel, 2000). AA and NIC reduced the anxiety levels, as seen in the reduced frequency of stretch attend posture.…”