Effectiveness of epigallocatechin gallate nanoparticles on the in-vivo treatment of Alzheimer's disease in a rat/mouse model: a systematic review.

BACKGROUND: Alzheimer's disease (AD) is a neurological disease that causes memory loss over time. Current therapies are limited and frequently inadequate. Epigallocatechin gallate (EGCG), has antioxidant, anti-inflammatory, antifibrosis, anti-remodeling and tissue-protective qualities that may be effective in treatment of different diseases, including AD. Because of nanoparticles' high surface area, they can enhance solubility, stability, pharmacokinetics and biodistribution, and diminish toxicities. Besides, lipid nanoparticles have a high binding affinity that can enhance the rate of drug transport across BBB. So, EGCG nanoparticles represent a promising treatment for AD. OBJECTIVES: This systematic review sought to assess the efficacy of EGCG nanoparticles against AD in rat/mouse models. METHODS: Study was conducted in accordance with PRISMA guidelines, and the protocol was registered in PROSPERO. Electronic databases were searched to discover relevant studies published up to October 2022. RESULTS: Two studies met the inclusion criteria out of 1338 and were included in this systematic review. Collectively, the results indicate that EGCG has a significant potential for reducing AD pathology and improving cognitive deficits in rat/mouse models. The formulated particles were in the nanometer range, as indicated by TEM, with good particle size control and stability. EGCG nanoparticles showed superior pharmacokinetic characteristics and improved blood-brain barrier permeability, and increased brain bioavailability compared to free EGCG. Additionally, nanoEGCG were more effective in modulating oxidative stress than free formulation and decreased AChE in the cortex and hippocampus of AlCl3-treated rats. CONCLUSION: This systematic analysis of the two studies included showed that EGCG nanoparticles are efficacious as a potential therapeutic intervention for AD in rat/mouse models. However, limited number of studies found indicates insufficient data in this research point that requires further investigation by experimental studies.

Further insights into the impact of rebamipide on gentamicin-induced nephrotoxicity in rats: modulation of SIRT1 and ß-catenin/cyclin D1 pathways.

Gentamicin (GM) is an effective antibiotic administered to treat acute Gram-negative infections. Nevertheless, its clinical application is limited due to nephrotoxicity. Therefore, our research aimed to investigate the potential renoprotective impact of rebamipide (RBM), a gastroprotective drug, on GM-induced kidney damage in rats, as well as putative nephroprotective pathways. RBM was orally administered (100 mg/kg/d for 14 d) commencing 7 d before the administration of GM (100 mg/kg/d, intraperitoneally). Nephrotoxicity was elucidated, and the silent information regulator 1 (SIRT1) and ß-catenin/cyclin D1 pathways were assessed. GM induced a significant elevation in the serum levels of creatinine, blood urea nitrogen (BUN), and kidney injury molecule-1 (KIM-1), as well as the relative kidney index. In addition, GM increased lipid peroxidation and lowered total antioxidant capacity (TAC) level and superoxide dismutase (SOD) activity. GM administration also demonstrated a significant amplification in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), nuclear factor-κappa B p65 (NF-κB p65), p38 mitogen-activated protein kinase (p38 MAPK), and caspase-3 kidney levels, as well as B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio. Notably, RBM treatment amended all these changes induced by GM. Furthermore, the potential role of SIRT1 and ß-catenin-dependent signaling pathways in GM-induced renal injury was assessed. Our findings showed that GM-treated rats demonstrated a substantial decrease in SIRT1, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) along with an increase in ß-catenin, forkhead box O-3a (FOXO-3a), and cyclin D1 protein expressions. RMB treatment markedly attenuated the deterioration caused by GM on these pathways. Additionally, RBM alleviated the GM-induced deleterious kidney tissue histopathology. In conclusion, our findings have verified that RBM can halt GM-induced renal injury by partly modulating SIRT1 and ß-catenin pathways.

Boswellic acids ameliorate neurodegeneration induced by AlCl3: the implication of Wnt/ß-catenin pathway.

Alzheimer's disease (AD) is a neurodegenerative disease (ND) that represents the principal cause of dementia. Effective treatment is still lacking. Without prevention, Alzheimer's disease (AD) incidence is expected to triple within 30 years. The risk increases in highly polluted areas and is positively linked to chronic aluminum (Al) exposure. Canonical Wingless-Int (Wnt)/ß-catenin pathway has been found to play a considerable role in ND pathogenesis. Resins of Boswellia serrata (frankincense) have been used traditionally for their psychoactive activity, in addition to their memory-boosting effects. Boswellic acids (BA) are pentacyclic triterpenes. They have antioxidant, anti-inflammatory, antinociceptive, and immunomodulatory activities. This study aimed to elucidate the role of the Wnt/ß-catenin pathway in BA protective activity against aluminum-induced Alzheimer's disease. For 6 weeks, rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with BA (125 or 250 mg/kg PO). Results indicated that BA significantly improved learning and memory impairments induced by AlCl3 treatment. Moreover, BA treatment significantly decreased acetylcholinesterase levels and reduced amyloid-beta (Aß) expression. In addition, BA ameliorated the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), inhibited lipid peroxidation, and increased total antioxidants in the brain. Indeed, BA significantly suppressed AlCl3-induced decrease of brain-derived neurotrophic factor, pGSK-3ß (Ser 9), and ß-catenin. BA (250 mg/kg) showed a significant protective effect compared to a lower dose. The results conclude that BA administration modulated the expression of Wnt/ß-catenin pathway-related parameters, contributing to BA's role against Al-induced Alzheimer's disease. Effect of Boswellic acids on AlCl3-induced neurodegenerative changes. ChE cholinesterase, Ach acetylcholine, BDNF brain-derived neurotrophic factor, IL-1ß interleukin-1ß, TNF-α tumor necrosis factor-α.

Sesame oil mitigates memory impairment, oxidative stress, and neurodegeneration in a rat model of Alzheimer's disease. A pivotal role of NF-κB/p38MAPK/BDNF/PPAR-γ pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Sesame (Sesamum indicum, L., Family: Pedaliaceae) is a notable folk medicine in Middle East, Asia and Africa. Many traditional and pharmacological studies have documented the unique nature of sesame oil (SO). SO has been reported to have many pharmacological effects related to the anti-inflammatory and antioxidant capacity of its components. Neuroinflammation and oxidative stress have been the predominant pathogenic events in Alzheimer's disease (AD) which is one of the most common neurodegenerative diseases. AIM OF STUDY: we aimed to explore the neuroprotective effect and the probable mechanisms of SO against aluminium chloride (AlCl3)-induced AD symptoms. MATERIALS AND METHODS: Rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with SO (two different doses) for six weeks. Behavioral (Open-field and Morris water maze tests), histopathological, and biochemical examinations were used to evaluate the neuroprotective effect and the underlying mechanisms of SO against AlCl3-induced AD symptoms. RESULTS: Our results indicated that SO significantly improved learning and memory impairments induced by AlCl3. Indeed, SO treatment significantly restored the elevated level of acetylcholinesterase (AChE) and amyloid beta (Aß) overexpression. Moreover, AlCl3 treatment afforded histopathological changes, increase the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in addition to mitigation of oxidative stress status in the brain. SO abolished all these abnormalities. Meanwhile, AlCl3 induced activation of p38 mitogen-activated protein kinase (p38MAPK) and decreased brain-derived neurotrophic factor (BDNF) which were inhibited by SO. Furthermore, SO administration modulated the expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) and nuclear factor kappa B (NF-κB). CONCLUSIONS: In conclusion, the neuroprotective effect of SO involved the modulation of different mechanisms targeting oxidative stress, neuroinflammation, and cognitive functions. SO may modulate different molecular targets involved in AD pathogenesis by alterations of NF-κB/p38MAPK/BDNF/PPAR-γ signalling and this may be attributed to the synergistic effect of their active components.

Cardioprotective effect of pioglitazone and curcumin against diabetic cardiomyopathy in type 1 diabetes mellitus: impact on CaMKII/NF-κB/TGF-ß1 and PPAR-γ signaling pathway.

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients, which is currently without available specific treatment. This study aimed to investigate the potential protective effects of pioglitazone (Pio) and curcumin (Cur) against DCM in type 1 diabetes mellitus (T1DM), with pointing to their role on Ca+2/calmodulin-dependent protein kinase II (CaMKII) and peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Diabetes was induced in adult male Sprague Dawley rats by administration of single intraperitoneal injection of streptozotocin (STZ) (52.5 mg/kg). Diabetic rats were administered either Pio (20 mg/kg/day) or Cur (100 mg/kg/day) orally for 6 weeks. Treatment with Pio and/or Cur markedly reduced serum cardiac injury markers and lipid profile markers in diabetic animals. Additionally, Pio and/or Cur treatment mitigated oxidative stress and fibrosis in diabetic rats as evident from the significant suppression in myocardial lipid peroxidation and tumor growth factor beta 1 (TGF-ß1) level, with concomitant significant elevation in total antioxidant capacity (TAC) and improvement in histopathological architecture of heart tissue. Pio/Cur treatment protocol accomplished its cardioprotective effect by depressing cardiac CaMKII/NF-κB signaling accompanied by enhancement in PPAR-γ expression. Conclusively, these findings demonstrated the therapeutic potential of Pio/Cur regimen in alleviating DCM in T1DM through modulation of CaMKII and PPAR-γ expression. Graphical Abstract.

Protective effect of irbesartan against doxorubicin-induced nephrotoxicity in rats: implication of AMPK, PI3K/Akt, and mTOR signaling pathways.

Nephrotoxicity is one of the serious undesirable effects related to doxorubicin (DOX). Herein, we have investigated the potential protective effect of irbesartan (IRB) against chronic nephrotoxicity induced by DOX, and the implication of different mechanistic pathways underlying these effects. Rats were treated with either DOX (2.5 mg/kg i.p., 3 times/week) for 2 weeks, and (or) IRB (40 mg/kg, daily) for 3 weeks. IRB prohibited nephrotoxicity induced by DOX, which was evident by the increase in blood urea nitrogen and creatinine levels and histopathological changes. IRB improved DOX-induced alterations in oxidative status by diminishing lipid peroxidation and upregulating the antioxidant enzymes. Also, upon DOX treatment, the renal expression of tumor necrosis factor-α, interleukin-6, and caspase-3 were significantly increased; IRB diminished DOX-induced alterations in these parameters. Moreover, DOX significantly decreased the expression level of AMP-activated protein kinase (AMPK). Meanwhile, DOX induced activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and mammalian target of rapamycin (mTOR) pathways that cross talked with AMPK. On the contrary, IRB successfully counterbalanced all these effects. Collectively, these outcomes suggest that the modulation of AMPK, PI3K, Akt, and mTOR pathways plays a critical role in conferring the protective effects of IRB against DOX nephrotoxicity.

Vinpocetine halts ketamine-induced schizophrenia-like deficits in rats: impact on BDNF and GSK-3ß/ß-catenin pathway.

There are increasing evidences supporting the involvement of oxidative stress and neuroinflammation in schizophrenia. Vinpocetine, a nootropic phosphodiesterase-1 inhibitor, was proven to possess anti-oxidant and anti-inflammatory potentials. This research aimed to reveal the likely protective features of vinpocetine against ketamine-induced schizophrenia-like deficits in rats. Additionally, the probable mechanisms contributing to this neuroprotection were also elucidated. Vinpocetine was given (20 mg/kg, i.p.) once a day for 14 days commencing 7 days before administrating ketamine (25 mg/kg i.p.). Risperidone was applied as a reference antipsychotic. Vinpocetine pre-treatment revealed a marked amendment in the hyperlocomotion, anxiety, and short-term memory deficits induced by ketamine in rats. In rats' hippocampus, ketamine induced a drastic increase in tissue levels of dopamine, lipid peroxidation, and pro-inflammatory cytokines along with a significant decrease in glutamate, GABA, SOD, and total anti-oxidant capacity. Also, ketamine induced a reduced level of BDNF together with the potentiation of GSK-3ß/ß-catenin pathway that led to the destruction of ß-catenin. Pre-treatment of ketamine-challenged animals with vinpocetine significantly attenuated oxidative stress, inflammation, and neurotransmitter alterations. Vinpocetine also elevated BDNF expression and prevented ketamine-induced stimulation of the GSK-3ß/ß-catenin signaling. This research presents enlightenments into the role of vinpocetine in schizophrenia. This role may be accomplished through its effect on oxidative stress, inflammation as well as modulating BDNF and the GSK-3ß/ß-catenin pathway.