Ashwagandha Diminishes Hippocampal Apoptosis Induced by Microwave Radiation by Acetylcholinesterase Dependent Neuro-Inflammatory Pathway in Male Coturnix coturnix Japonica.

Microwave radiation (MWR) has been linked to neurodegeneration by inducing oxidative stress in the hippocampus of brain responsible for learning and memory. Ashwagandha (ASW), a medicinal plant is known to prevent neurodegeneration and promote neuronal health. This study investigated the effects of MWR and ASW on oxidative stress and cholinergic imbalance in the hippocampus of adult male Japanese quail. One control group received no treatment, the second group quails were exposed to MWR at 2 h/day for 30 days, third was administered with ASW root extract orally 100 mg/day/kg body weight and the fourth was exposed to MWR and also treated with ASW. The results showed that MWR increased serum corticosterone levels, disrupted cholinergic balance and induced neuro-inflammation. This neuro-inflammation further led to oxidative stress, as evidenced by decreased activity of antioxidant enzymes SOD, CAT and GSH. MWR also caused a significant decline in the nissil substances in the hippocampus region of brain indicating neurodegeneration through oxidative stress mediated hippocampal apoptosis. ASW, on the other hand, was able to effectively enhance the cholinergic balance and subsequently lower inflammation in hippocampus neurons. This suggests that ASW can protect against the neurodegenerative effects of MWR. ASW also reduced excessive ROS production by increasing the activity of ROS-scavenging enzymes. Additionally, ASW prevented neurodegeneration through decreased expression of caspase-3 and caspase-7 in hippocampus, thus promoting neuronal health. In conclusion, this study showed that MWR induces apoptosis and oxidative stress in the brain, while ASW reduces excessive ROS production, prevents neurodegeneration and promotes neuronal health.

Folic acid improved memory and learning function in a rat model of neuroinflammation induced by lipopolysaccharide.

Folic acid (FA) plays an important role in the maintenance of normal neurological functions such as memory and learning function. Neuroinflammation contributes to the progression of cognitive disorders and Alzheimer's disease. Thus, this study aimed to investigate the effect of FA supplementation on cognitive impairment, oxidative stress, and neuro-inflammation in lipopolysaccharide (LPS)-injured rats. For this purpose, the rats were given FA (5-20 mg/kg/day, oral) for 3 weeks. In the third week, LPS (1 mg/kg/day; intraperitoneal injection) was given before the Morris water maze (MWM) and passive avoidance (PA) tests. Finally, the brains were removed for biochemical assessments. In the MWM test, LPS increased the escape latency and traveled distance to find the platform compared to the control group, whereas all doses of FA decreased them compared to the LPS group. The findings of the probe trial showed that FA increased the traveling time and distance in the target area. LPS impaired the performance of the rats in the PA test. FA increased delay and light time while decreasing the frequency of entry and time in the dark region of PA. LPS increased hippocampal levels of interleukin (IL)-6 and IL-1ß. The hippocampal level of malondialdehyde was also increased but thiol content and superoxide dismutase activity were decreased in the LPS group. However, treatment with FA restored the oxidative stress markers along with a reduction in the levels of pro-inflammatory cytokines. In conclusion, FA could ameliorate the memory and learning deficits induced by LPS via normalizing the inflammatory response and oxidative stress markers in the brain.

Long-Term Krill Oil Administration Alleviated Early Mild Cognitive Impairment in APP/PS1 Mice.

SCOPE: Alzheimer's disease is an age-dependent neurodegenerative disorder. Mounting studies focus on the improvement of advanced cognitive impairment by dietary nutrients. Krill oil (KO), a rich source of DHA/EPA and astaxanthin, is effective in improving cognitive function. The study mainly investigates the protective effects of long-term KO administration on early cognitive impairment. METHODS AND RESULTS: Results show that 2 months KO administration (50 and 100 mg kg-1 BW) can dramatically promote learning and memory abilities. Mechanism studies demonstrate that KO reduces amyloid ß concentration by regulating the amyloidogenic pathway, inhibits neuro-inflammation via regulating TLR4-NLRP3 signaling pathway, and prevents neuron injure. KO supplementation also enhances gut barrier integrity, reduces serum lipopolysaccharide leakage, and alters the gut microbiota by reducing Helicobacteraceae, Lactobacillaceae proportion, increasing Dubosiella and Akkermansia relative abundance. Particularly, a significant increase of isovaleric acid, propionic acid, and acetic acid levels is observed after KO supplementation. Correlation analysis shows that short-chain fatty acids (SCFAs), gut microbiota, and cognitive function are strongly correlated. CONCLUSIONS: The results reveal that KO relieves early mild cognitive impairment possibly for its role in mediating the gut microbiome-SCFAs-brain axis. Thus, KO may provide potential intervention strategies to prevent cognitive impairment in the early stages through the microbiota-gut-brain axis.

Therapeutic potential of flavonoids in the management of obesity-induced Alzheimer's disease: an overview of preclinical and clinical studies.

Obesity is a global epidemic that affects people of all ages, genders, and backgrounds. It can lead to a plethora of disorders, including diabetes mellitus, renal dysfunction, musculoskeletal problems, metabolic syndrome, cardiovascular, and neurodegenerative abnormalities. Obesity has also been linked to neurological diseases such as cognitive decline, dementia, and Alzheimer's disease (AD), caused by oxidative stress, pro-inflammatory cytokines, and the production of reactive oxygen free radicals (ROS). Secretion of insulin hormone is impaired in obese people, leading to hyperglycaemia and increased accumulation of amyloid-ß in the brain. Acetylcholine, a key neurotransmitter necessary for forming new neuronal connections in the brain, decreases in AD patients. To alleviate acetylcholine deficiency, researchers have proposed dietary interventions and adjuvant therapies that enhance the production of acetylcholine and assist in the management of AD patients. Such measures include dietary intervention with antioxidant and anti-inflammatory flavonoid-rich diets, which have been found to bind to tau receptors, reduce gliosis, and reduce neuroinflammatory markers in animal models. Furthermore, flavonoids like curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, and oleocanthal have shown to cause significant reductions in interleukin-1ß, increase BDNF levels, stimulate hippocampal neurogenesis and synapse formation, and ultimately prevent the loss of neurons in the brain. Thus, flavonoid-rich nutraceuticals can be a potential cost-effective therapeutic option for treating obesity-induced AD, but further well-designed, randomized, and placebo-controlled clinical studies are needed to assess their optimal dosages, efficacy, and long-term safety of flavonoids in humans. The main objectives of this review are to underscore the therapeutic potential of different nutraceuticals containing flavonoids that can be added in the daily diet of AD patients to enhance acetylcholine and reduce neuronal inflammation in the brain.

Withaferin A for COVID-19: a Network Pharmacology Approach.

COVID-19 has become a global challenge as there are very few treatment options available. This has proved to impact several physiological implications like immunological injury, myocardial infarction, micro-thrombus formation, neurological complications and multi-organ dysfunction. A combination therapy or a systems pharmacology approach can be adopted to fight against COVID-19. Here, we have proposed withaferin A as a system pharmacophore employing molecular docking strategy using AutoDock Vina and utilising different bioinformatics tools like PharmMapper, STRING database and PANTHER Pathway enrichment analysis. Docking results show that withaferin A exhibits a significant binding affinity with P2Y12 receptor, vitamin D-binding protein and annexin A5, hence implying that it could play a role in anti-thrombosis. Protein-protein interaction network showed its importance in innate immune system. Results also show that this molecule may have significant potential to modulate T cell activation too. Text mining results showed association of STAT3 with withaferin A. Our studies propose that withaferin A might also conquer the cytokine storm via STAT3. This study concludes that two strong targets of withaferin A, i.e. vitamin D-binding protein and STAT3, have been identified and that withaferin A can be used as a system pharmacophore for drug development in order to combat COVID-associated complicacies.

[Electroacupuncture inhibits neuron injury of SAMP8 mice by reducing inflammatory response].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Baihui"(GV20) and "Shenshu" (BL23) on the pathological injury of neurons in SAMP8 mice and the anti-inflammatory effect on neuron repair, providing a new experimental basis for EA prevention and treatment of Alzheimer's disease. METHODS: Twelve 7-month-old SAMP8 mice were randomly divided into model and EA groups, and 6 SAMR1 mice of the same age and genetic background were used as normal group. Mice in the EA group were needled at GV20 and bilateral BL23, and EA (1 mA, 2 Hz) was applied to bilateral BL23 for 15 min, once daily, 10 d as a course for a total of 4 courses, with an interval of 1 d. Mice in the normal and model groups were captured and fixed in the same way as the EA group. The spatial learning and memory ability was detected by Morris water maze test. Neuronal nuclear antigen (NeuN) positive expression and the number of NeuN-positive cells in dentate gyrus (DG) were detected by immunofluorescence staining. The protein expression levels of ionized calcium binding adapter molecule 1(Iba-1), tumor necrosis factor-α(TNF-α), interleukin (IL)-6 and IL-1ß in hippocampus were detected by Western blot. The ultrastructure of nerve cells in DG was observed by transmission electron microscopy. RESULTS: Compared with the normal group, the average escape latency was prolonged(P<0.01), the number of platform crossing was significantly reduced (P<0.01), the average fluorescence intensity of NeuN and the number of NeuN-positive cells in hippocampus DG region decreased (P<0.05), the expression levels of Iba-1, TNF-α, IL-6 and IL-1ß in hippocampus were increased (P<0.05) in the model group.Compared with the model group, the ave-rage escape latency was shortened (P<0.01), the number of platform crossing times was significantly increased (P<0.01), the average fluorescence intensity of NeuN and the number of NeuN-positive cells in hippocampus DG region increased (P<0.05), the expression levels of Iba-1, TNF-α, IL-6 and IL-1ß in hippocampus were decreased (P<0.05) in the EA group. The morphology of nerve cells in the hippocampus DG region was normal， and the organelles in the cytoplasm were clear, complete and regularly distributed in the normal group. However, the morphology of nerve cells in the model group was seriously irregular, which was also irregular in EA group but somewhat relieved compared with model group. CONCLUSION: EA at GV20 and BL23 can improve the learning and memory ability of SAMP8 mice, which may be related to inhibiting the neuroinflammatory response, increasing the number of neurons and improving the ultrastructure of the DG region of the hippocampus to play the role of neuron protection.

Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases.

Some of the greatest challenges in medicine are the neurodegenerative diseases (NDs), which remain without a cure and mostly progress to death. A companion study employed a toolkit methodology to document 2001 plant species with ethnomedicinal uses for alleviating pathologies relevant to NDs, focusing on its relevance to Alzheimer's disease (AD). This study aimed to find plants with therapeutic bioactivities for a range of NDs. 1339 of the 2001 plant species were found to have a bioactivity from the literature of therapeutic relevance to NDs such as Parkinson's disease, Huntington's disease, AD, motor neurone diseases, multiple sclerosis, prion diseases, Neimann-Pick disease, glaucoma, Friedreich's ataxia and Batten disease. 43 types of bioactivities were found, such as reducing protein misfolding, neuroinflammation, oxidative stress and cell death, and promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, and anti-microbial activity. Ethno-led plant selection was more effective than random selection of plant species. Our findings indicate that ethnomedicinal plants provide a large resource of ND therapeutic potential. The extensive range of bioactivities validate the usefulness of the toolkit methodology in the mining of this data. We found that a number of the documented plants are able to modulate molecular mechanisms underlying various key ND pathologies, revealing a promising and even profound capacity to halt and reverse the processes of neurodegeneration.

Cornuside, by regulating the AGEs-RAGE-IκBα-ERK1/2 signaling pathway, ameliorates cognitive impairment associated with brain aging.

Anti-Alzheimer's disease (AD) drugs can only change the symptoms of cognitive impairment in a short time but cannot prevent or completely cure AD. Thus, a more effective drug is urgently needed. Cornuside is extracted from Corni Fructus, a traditional Chinese medicine that plays an important role in treating dementia and other age-related diseases. Thus, the study aimed to explore the effects and mechanisms of Cornuside on the D-galactose (D-Gal) induced aging mice accompanied by cognitive decline. Initially, we found that Cornuside improved the learning and memory abilities of D-Gal-treated mice in behavioral experiments. Pharmacological experiments indicated that Cornuside acted on anti-oxidant and anti-inflammatory effects. Cornuside also reversed acetylcholin esterase (AChE) activity. Meanwhile, pathology tests showed that Cornuside had a protective effect on neuron damage. Cornuside increased the expression of brain-derived neurotrophic factor (BDNF), and down-regulated the expression of receptor for advanced glycosylation end products (RAGE), ionized calcium binding adapter molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) respectively. Further studies claimed that Cornuside had important effects on the expression of IκBα and extracellular signal-regulated kinases 1/2 (ERK1/2). These effects might be achieved through regulating the AGEs-RAGE-IκBα-ERK1/2 signaling pathway, among which, ERK1/2 might be the key protein. The study provides direct preclinical evidence for the research of Cornuside, which may become an excellent candidate drug for the treatment of aging-related AD.

Leaf extract of Anacardium occidentale ameliorates biomarkers of neuroinflammation, memory loss, and neurobehavioral deficit in N(ω)-nitro-L-arginine methyl ester (L-NAME) treated rats.

PURPOSE: Anacardium occidentale commonly known as Cashew is a plant that is widely used in African traditional medicine. It is endowed with phytochemical constituents that are responsible for its medicinal properties. METHODS: Twenty-five male Wistar rats were grouped as follows: Control (Group A), Group B (L-NAME 40 mg/kg), Group C (100 mg/kg Anacardium occidentale extract plus 40 mg/kg L-NAME), Group D (200 mg/kg extract plus 40 mg/kg L-NAME) and Group E (10 mg/kg of Lisinopril plus 40 mg/kg L-NAME). The animals were treated with oral administration of either the extracts or Lisnopril daily for 4 weeks. Neuro-behavioural tests such as the Morris Water Maze and Hanging Wire Grip tests were carried out to evaluate memory/spatial learning and muscular strength, respectively. Makers of oxidative stress, antioxidant enzymes and immunohistochemical staining of Glial Fibrillary Acidic Protein and Ionised Calcium Binding Adaptor molecule 1 were assessed. RESULTS: L-NAME administration caused significant increases in biomarkers of oxidative stress, decreased antioxidant status, acetylcholinesterase activity, altered neuro-behavioural changes, astrocytosis, and microgliosis. However, Anacardium occidentale reversed exaggerated oxidative stress biomarkers and improved neuro-behavioural changes. CONCLUSIONS: Combining all, Anacardium occidentale enhanced brain antioxidant defence status, improved memory and muscular strength, thus, suggesting the neuroprotective properties of Anacardium occidentale.

Achyranthes aspera ameliorates stress induced depression in mice by regulating neuroinflammatory cytokines.

Background and aim: Achyranthes aspera Linn. (A. aspera) (family: Amaranthaceae) is highly recognized in ethnomedicine and traditional systems of Indian medicine as a nervine restorative for several psychiatric disorders. Study presented here was designed to appraise the antidepressant-like effects of A. aspera in murine model of chronic unpredictable mild stress (CUMS) induced depression. Experimental procedures-: Rodents were exposed to different stressor in unpredictive manner during CUMS protocol once a day for 4 weeks. Mice were intraperitoneally injected with A. aspera extract (2.5, 5 and 10 mg/kg) or fluoxetine (10 mg/kg) or betaine (20 mg/kg) once daily during day 15-28 of the CUMS protocol. Sucrose preference, motivation and self-care, immobility latency and plasma corticosterone were evaluated after 24 h of last stressor. After behavioral assessments TNF-α, Il-6 and BDNF immunocontent was determined in hippocampus and prefrontal cortex. Results and conclusion: A. aspera extract as well as betaine improved sucrose preference, increased grooming frequency and latency in splash test and ameliorated depression-like condition in CUMS mice in Porsolt test. A. aspera treatment decreased the elevated plasma corticosterone and reversed the effect of CUMS on TNF-α, Il-6 and BDNF immunocontent in mice. The results of the present study suggest A. aspera as a promising indigenous medicine for stress associated neurobehavioral and comorbid complications.

Aloe vera and Fermented Extracts Exhibit an Anti-Inflammatory Effect on Human Glioblastoma/Astrocytoma U373 MG Cells.

The anti-inflammatory effects of Aloe vera (AV), polysaccharide extract from AV, and extracts from the digestion and colonic fermentation of AV were evaluated using an immortal astrocyte cell line (U373 MG) that develops a neuro-inflammatory profile. Cell viability and inflammatory markers were assessed after stimulation with neuropeptide substance P (SP) that activates the pro-inflammatory MAPK (mitogen-activated protein kinase) pathway. Cell viability after SP treatment was over 50% at 10 mg/mL AV, polysaccharide extract from AV, extracts from the digestion: non-digestible fraction of AV non-digestible fraction of polysaccharide extract from AV and extracts from the colonic fermentation of AV, at 4 and 24 h. Moreover, cells exposed to SP and treated with these extracts showed lower protein-activated ERK1/ERK2 (extracellular signal-regulated kinases 1 and 2), p38 (MAPK protein p38), and NFκB (nuclear factor κB) levels with respect to the SP-stimulated control. Inflammation inhibition by extracts of polysaccharide extract from AV and extracts from the colonic fermentation of AV, at 24 h in the study of p38 was not as statistically significant in ERK1/ERK2 and NFκB. Nevertheless, there was a significant decrease (p < 0.05) in pro-inflammatory cytokine IL-6 levels in cells exposed to all samples. Samples with extracts from the colonic fermentation of AV, at 4 or 24 h showed the highest inhibitory effect on IL-6 production.

Neuroprotective effect of the standardised extract of Bacopa monnieri (BacoMind) in valproic acid model of autism spectrum disorder in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Bacopa monnieri (BM) is commonly employed in the Indian traditional system of medicines, i.e. Ayurveda as a memory booster, antioxidant, anti-inflammatory, antipyretic, analgesic, sedative and anti-epileptic for decades. AIM OF THE STUDY: To evaluate the neuroprotective effect of Bacopa monnieri (BM) in experimental model of autism spectrum disorder (ASD) in Wistar rats and explore its mechanism of action. MATERIALS AND METHODS: BacoMind, was evaluated for its neuroprotective effect in valproic acid (VPA) model of ASD. For in-vivo study, the pregnant female Wistar rats were divided in two groups; normal control (NC) and VPA group who received single dose of normal saline (0.9%) or 600 mg/kg dose of VPA respectively on gestation day (G.D) 12.5. After the birth, all pups were segregated according to the sex. All the male pups from the dams were divided into six groups: Group 1 (NC, treated with only 0.9% normal saline, group 2 (VPA, treated 600 mg/kg on G.D12.5 and normal saline from post natal day (PND) 23 to 43), group 3 (risperidone 2.5 mg/kg, PND 23 to 43) and groups 4, 5 and 6 (BM 20, 40, 80 mg/kg, PND 23 to 43). All experimental groups were subjected to batteries of behavior parameters (three chamber sociability test, Morris Water Maze, elevated plus maze, open field and rota rod test), biochemical parameters such as oxidative stress (GSH, SOD, Catalase, MDA), inflammatory cytokines (Il-1ß, IL-6, IL-10, TNF-α), histopathological examination (cresyl violet staining) of hippocampus (HC) and prefrontal cortex (PFC) regions. Further, the mRNA as well as protein expression of AMPA receptor was evaluated using RT-PCR and western blot respectively to study the mechanism of neuroprotective effect of BM. The in-silico analysis followed evaluating the binding profile of different constituents of BacoMind with AMPA receptor. RESULTS: The results of the in-vivo study indicated BM at 80 mg/kg ameliorated abnormal behavioral paradigms such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination exhibited by the VPA model of ASD in rats. Furthermore, BM was found to have a significant anti-oxidant (increasing GSH, SOD, and catalase and decreasing MDA levels) and anti-inflammatory properties (decreasing IL-1ß, 6, TNF- α). The histopathological score was also found to be significantly improved by BM in a dose dependent manner in both HC and PFC. In addition to this, the up-regulated mRNA as well as protein expression of AMPA receptor was significantly reduced by 80 mg/kg dose of BM in both HC and PFC. Further, the in-silico analysis of different constituents of BacoMind with AMPA receptor demonstrated that luteolin and apigenin showed good binding to both the competitive antagonist binding site, non-competitive antagonist binding site and allosteric modulator site while Bacosaponin C showed good binding to the non-competitive antagonist binding site. CONCLUSION: The present study concluded that BM can be a potential candidate for ameliorating the ASD symptoms in rats and acts via modulating the up-regulated AMPA receptor expression.

Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.

Multiple sclerosis (MS) is a chronic and complex neurodegenerative disease, distinguished by the presence of lesions in the central nervous system (CNS) due to exacerbated immunological responses that inflict oligodendrocytes and the myelin sheath of axons. In recent years, studies have focused on targeted therapeutics for MS that emphasize the role of G protein-coupled receptors (GPCRs), specifically cannabinoids receptors. Clinical studies have suggested the therapeutic potential of cannabinoids derived from Cannabis sativa in relieving pain, tremors and spasticity. Cannabinoids also appear to prevent exaggerated immune responses in CNS due to compromised blood-brain barrier. Both, endocannabinoid system (ECS) modulators and cannabinoid ligands actively promote oligodendrocyte survival by regulating signaling, migration and myelination of nerve cells. The cannabinoid receptors 1 (CB1) and 2 (CB2) of ECS are the main ones in focus for therapeutic intervention of MS. Various CB1/CB2 receptors agonists have been experimentally studied which showed anti-inflammatory properties and are considered to be effective as potential therapeutics for MS. In this review, we focused on the exacerbated immune attack on nerve cells and the role of the cannabinoids and its interaction with the ECS in CNS during MS pathology.

Melatonin salvages lead-induced neuro-cognitive shutdown, anxiety, and depressive-like symptoms via oxido-inflammatory and cholinergic mechanisms.

INTRODUCTION: Lead is the most used nonphysiological neurotoxic heavy metal in the world that has been indicated to interfere with the cognitive and noncognitive processes via numerous mechanisms. The neuroprotective effect of melatonin is well known, but the effect of its interaction with lead in the brain remains inconclusive. OBJECTIVE: To assess the therapeutic role of melatonin on cognitive deficit, anxiety and depressive-like symptoms in matured male Wistar rats exposed to a subchronic lead chloride (PbCl2 ). METHODS: Twenty male Wistar rats were blindly randomized into four groups (n = 5/group): group 1 to 4 underwent intragastric administration of physiological saline (10 ml/kg; vehicle), PbCl2 (50 mg/kg), melatonin (10 mg/kg) and PbCl2 + melatonin respectively for a period of 4 weeks during which neurobehavioral data were extracted, followed by neurochemical and histopathological evaluations. RESULTS: Exposure to PbCl2 reduced cognitive performance by increasing the escape latency and average proximity to the platform zone border, decreasing average path length in the platform zone, cognitive score, and time spent in probing. It raised the thigmotaxis percentage, time spent in rearing, number of pellet-like feces, and time spent in the dark compartment of a bright/dark box which are predictors of anxiety. It also induced depressive-like behavior as immobility time was enhanced. PbCl2 deranged neurochemicals; malondialdehyde, interlukin-1ß, and tumor necrotic factor-α were increased while superoxide dismutase and acetylcholinesterase were decreased without remarkable alteration in reduced glutathione and nitric oxide. Administration of PbCl2 further disrupted neuronal settings of hippocampal proper and dentate gyrus. In contrast, the supplementation of melatonin reversed all the neurological consequences of PbCl2 neurotoxicity by eliciting its properties against oxidative and nonoxidative action of PbCl2 . CONCLUSION: These findings suggest that melatonin down-regulates neurotoxicant interplays in the brain systems. Therefore, this study suggests the use of melatonin as an adjuvant therapy in neuropathological disorders/dysfunctions.

Possible role of rice bran extract in microglial modulation through PPAR-gamma receptors in alzheimer's disease mice model.

Alzheimer's Disease (AD), the most prevalent neurodegenerative disorder among elderly people, is ordinarily associated with progressive cognitive decline. Peroxisome proliferator-activated receptors-gamma (PPAR-γ) agonists can be targeted as a beneficial therapeutic strategy against AD. In the present study, we aimed to investigate the preventive and therapeutic effects of rice bran extract (RBE) as a possible PPAR-γ agonist on the microglial phenotype modulation in AD in mice compared to the effects of pioglitazone. This study included 64 adult male Swiss Albino mice divided into 8 groups, each group comprised 8 mice; control group, RBE group, lipopolysaccharide-induced neurodegeneration (a) (LPSa) group, (LPSb) group, RBE-preventive group (RBE + LPSa), pioglitazone-preventive group (PG + LPSa), RBE-treated group (RBE + LPSb), and pioglitazone-treated group (PG + LPSb). Cognitive functions were assessed by Y-maze and Morris water maze tests. The expression of PPAR-γ, CD45, arginase1, CD36, and CD163 genes was assessed by real time qPCR and the estimation of NF-kß protein level was done by Western blot technique. Moreover, the assessment of Aß42 and P-tau levels was performed by ELISA. Histopathological examination of brain tissues was performed for all the studied groups. Our results showed that RBE and pioglitazone could modulate microglial phenotype from M1 to M2 where they significantly decreased the expression of NF-κß and the pro-inflammatory microglial marker (CD45) in parallel with increasing the expression of the anti-inflammatory microglial and phagocytic markers (arginase1, CD163, and CD36). In addition, RBE and pioglitazone significantly increased PPAR-γ expression and reduced Aß42 deposition as well as p-tau protein levels. In conclusion, our study identified the possible role of PPAR-γ agonistic activity of RBE as a preventive and therapeutic agent in the treatment of the neuro-inflammation associated with AD.

Ursolic and Oleanolic Acids: Plant Metabolites with Neuroprotective Potential.

Ursolic and oleanolic acids are secondary plant metabolites that are known to be involved in the plant defence system against water loss and pathogens. Nowadays these triterpenoids are also regarded as potential pharmaceutical compounds and there is mounting experimental data that either purified compounds or triterpenoid-enriched plant extracts exert various beneficial effects, including anti-oxidative, anti-inflammatory and anticancer, on model systems of both human or animal origin. Some of those effects have been linked to the ability of ursolic and oleanolic acids to modulate intracellular antioxidant systems and also inflammation and cell death-related pathways. Therefore, our aim was to review current studies on the distribution of ursolic and oleanolic acids in plants, bioavailability and pharmacokinetic properties of these triterpenoids and their derivatives, and to discuss their neuroprotective effects in vitro and in vivo.

Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer.

Alzheimer's disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-ß (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3 µg/3 µl) and after with Ribodiet® (0.1-10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100ß, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.

Potential anti-neuroinflammatory compounds from Australian plants - A review.

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators, such as cytokines and chemokines, and generation of reactive oxygen and nitrogen species. Even though it is considered an event secondary to neuronal death or dysfunction, neuro-inflammation comprises a majority of the non-neuronal contributors to the cause and progression of neurodegenerative diseases like Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Chronic Traumatic Encephalopathy (CTE) and others. As a result of the lack of effectiveness of current treatments for neurodegenerative diseases, neuroinflammation has become a legitimate therapeutic target for drug discovery, leading to the study of various in vivo and in vitro models of neuroinflammation. Several molecules sourced from plants have displayed anti-inflammatory properties in the study of neurodegenerative diseases. A group of these anti-inflammatory compounds has been classified as cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the pro-inflammatory AP1 and nuclear factor-κB signaling pathways and inhibit the expression of many pro-inflammatory cytokines, such as interleukin IL-1, IL-6, TNF-α, or nitric oxide. Australian plants, thriving amid the driest inhabited continent of the world, are an untapped source of chemical diversity in the form of secondary metabolites. These compounds are produced in response to biotic and abiotic stresses that the plants are exposed to in the highly biodiverse environment. This review is an attempt to highlight anti-inflammatory compounds isolated from Australian plants.

Vitamin D: A Pleiotropic Hormone with Possible Psychotropic Activities.

BACKGROUND: After the recognition of the efficacy of cod-liver oil in rickets at the end of the eighteenth century, and the isolation and synthesis of the liposoluble vitamin D in 1931, its mode of actions and functions were deeply explored. Biochemical studies permitted to identify five forms of vitamin D, called D1, D2, D3, D4 and D5, differing in ultrastructural conformation and origin, with vitamin D2 (ergocalciferol) and D3 (cholecalciferol) representing the active forms. In the last decades especially, a constantly increasing bulk of data highlighted how vitamin D could regulate several activities and processes. AIMS: The aim of the present paper was to review and comment on the literature on vitamin D, with a focus on its possible role in the pathophysiology of neuropsychiatric disorders. DISCUSSION: Available literature indicates that vitamin D regulates a variety of processes in humans and in the central nervous system. Vitamin D deficiency is associated with an enhanced pro-inflammatory state, and formation of Aß oligomers that might contribute to the cognitive decline typical of the elderly age and, perhaps, dementia. More in general, vitamin D is supposed to play a crucial role in neuroinflammation processes that are currently hypothesized to be involved in the pathophysiology of different psychiatric disorders, such as major depression, bipolar disorders, obsessive-compulsive disorders and psychosis. CONCLUSION: It is conceivable that vitamin D supplementation might pave the way towards "natural" treatments of a broad range of neuropsychiatric disorders, or at least be useful to boost response to psychotropic drugs in resistant cases.

Magnetic resonance assessment of the cerebral alterations associated with obesity development.

Obesity is a current threat to health care systems, affecting approximately 13% of the world's adult population, and over 18% children and adolescents. The rise of obesity is fuelled by inadequate life style habits, as consumption of diets rich in fats and sugars which promote, additionally, the development of associated comorbidities. Obesity results from a neuroendocrine imbalance in the cerebral mechanisms controlling food intake and energy expenditure, including the hypothalamus and the reward and motivational centres. Specifically, high-fat diets are known to trigger an early inflammatory response in the hypothalamus that precedes weight gain, is time-dependent, and eventually extends to the remaining appetite regulating regions in the brain. Multiple magnetic resonance imaging (MRI) and spectroscopy (MRS) methods are currently available to characterize different features of cerebral obesity, including diffusion weighted, T2 and volumetric imaging and 1H and 13C spectroscopic evaluations. In particular, consistent evidences have revealed increased water diffusivity and T2 values, decreased grey matter volumes, and altered metabolic profiles and fluxes, in the brain of animal models and in obese humans. This review provides an integrative interpretation of the physio-pathological processes associated with obesity development in the brain, and the MRI and MRS methods implemented to characterize them.