Rat Model Of Disease Research Articles

Effects of hippocampal damage on pain perception in a rat model of Alzheimer's disease induced by amyloid-β and ibotenic acid injection into the hippocampus

Patients with Alzheimer's disease (AD) present with a variety of symptoms, including core symptoms as well as behavioral and psychological symptoms. Somatosensory neural systems are generally believed to be relatively unaffected by AD until late in the course of the disease; however, somatosensory perception in patients with AD is not yet well understood. One factor that may complicate the assessment of somatosensory perception in humans centers on individual variations in pathological and psychological backgrounds. It is therefore necessary to evaluate somatosensory perception using animal models with uniform status. In the current study, we focused on the hippocampus, the primary site of AD. We first constructed a rat model of AD model using bilateral hippocampal injections of amyloid-β peptide 1–40 and ibotenic acid; sham rats received saline injections. The Morris water maze test was used to evaluate memory impairment, and the formalin test (1 % or 4 % formalin) and upper lip von Frey test were performed to compare pain perception between AD model and sham rats. Finally, histological and immunohistochemical methods were used to evaluate tissue damage and neuronal activity, respectively, in the hippocampus. AD model rats showed bilateral hippocampal damage and had memory impairment in the Morris water maze test. Furthermore, AD model rats exhibited significantly less pain-related behavior in phase 2 (the last 50 min of the 60-minute observation) of the 4 % formalin test compared with the sham rats. However, no significant changes were observed in the von Frey test. Immunohistochemical observations of the trigeminal spinal subnucleus caudalis after 4 % formalin injection revealed significantly fewer c-Fos-immunoreactive cells in AD model rats than in sham rats, reflecting reduced neuronal activity. These results indicate that AD model rats with hippocampal damage have reduced responsiveness to persistent inflammatory chemical stimuli to the orofacial region.

Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in a rat model of Alzheimer's disease.

Ginkgo biloba extracts (GBE) have been shown to effectively improve cognitive function in patients with Alzheimer's disease (AD). One potential therapeutic strategy for AD is to prevent loss of adult hippocampal neurons. While recent studies have reported that GBE protects against oxidative stress in neurons, the underlying mechanisms remain unclear. In this study, an AD-like rat model was established via bidirectional injection of amyloid beta 25-35 (Aβ25-35; 20 μg) in the hippocampal CA1 region. Learning and memory abilities of experimental rats were AD assessed in response to oral administration of 7.5 g/L or 15 g/L Ginkgo biloba extract 50 (GBE50) solution and the peroxidation phenomenon of hippocampal mitochondria determined via analysis of mitochondrial H2O2 and several related enzymes. Levels of the oxidative stress-related signaling factor cytochrome C (Cyto C), apoptosis-related proteins (Bax, Bcl-2 and caspase-3) and caspase-activated DNase (CAD) were further detected via western blot. 8-Hydroxydeoxyguanosine (8-OHdG), the major product of DNA oxidative stress, was evaluated to analyze DNA status. Our results showed elevated H2O2 levels and monoamine oxidase (MAO) activity, and conversely, a decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampus of AD rats. Administration of GBE50 regulated the activities of these three enzymes and induced a decrease in H2O2. GBE50 exerted regulatory effects on abnormally expressed apoptotic proteins in the AD rat hippocampus, enhancing the expression of Bcl-2, inhibiting release of Cyto C from mitochondria, and suppressing the level of caspase-3 (excluding cleaved caspase-3). Furthermore, GBE50 inhibited DNA damage by lowering the generation of 8-OHdG rather than influencing expression of CAD. The collective findings support a protective role of GBE50 in hippocampal neurons of AD-like animals against mitochondrial oxidative stress.

Montelukast Ameliorates Scopolamine-induced Alzheimer's Disease: Role on Cholinergic Neurotransmission, Antioxidant Defence System, Neuroinflammation and Expression of BDNF.

Alzheimer's disease (AD) is an overwhelming neurodegenerative disease with progressive loss of memory. AD is characterized by the deposition of the senile plaques mainly composed of β-amyloid (Aβ) fragment, BDNF decline, Cholinergic system overactivity and neuroinflammation. Montelukast (MTK), a leukotriene receptor antagonist, showed astounding neuroprotective effects in a variety of neurodegenerative disorders. This study aims to investigate the ameliorative effects of Montelukast in the scopolamineinduced Alzheimer's disease (AD) model in rats and evaluate its activity against neuroinflammation. Thirty rats were split into five groups: Control group (1 mL/kg normal saline, i.p.), Montelukast perse (10 mg/kg, i.p.), Disease group treated with Scopolamine (3 mg/kg, i.p.), Donepezil group (3 mg/kg, i.p.), Montelukast treatment group (10 mg/kg, i.p.) and behavioural and biochemical tests were carried out to assess the neuro protective effect. Scopolamine treatment led to a significant reduction in learning and memory and an elevation in cholinesterase levels when compared with the control group (p < 0.01). Additionally, elevated oxidative stress and Amyloid-β levels were associated with enhanced neuroinflammation (p < 0.05, p < 0.01). Furthermore, the decline in neurotrophic factor BDNF is also observed when compared with the normal control group (p < 0.01). Montelukast pre-treatment significantly attenuated learning and memory impairment and cholinesterase levels. Besides, Montelukast and standard drug donepezil administration significantly suppressed the oxidative stress markers (p < 0.01), Amyloid-β levels, neuroinflammatory mediators (p < 0.05) and caused a significant increase in BDNF levels (p < 0.05). Montelukast bestowed ameliorative effects in scopolamine-induced AD animal models as per the previous studies via attenuation of memory impairment, cholinesterase neurotransmission, oxidative stress, Amyloid-β levels, neuroinflammatory mediators and enhanced BDNF levels.

Reversal of heavy arterial calcification in a rat model of chronic kidney disease using targeted ethylene diamine tetraacetic acid-loaded albumin nanoparticles.

Elastin degradation and severe calcification in the medial layer of the vessel wall, known as medial arterial calcification (MAC), is typical in the aging population and patients with metabolic disorders, such as diabetes and chronic kidney disease (CKD). We have previously reported that ethylene diamine tetraacetic acid (EDTA) delivery to the site of calcification can be achieved by tagging nanoparticles with an elastin antibody that recognizes explicitly damaged elastin, and such systemic therapy can remove focal calcium deposits from the calcified arteries in CKD rodent model. The current study aims to test whether heavy calcification seen throughout arterial tree and kidneys in CKD can be reversed with nanoparticle therapy. Thirty healthy male Sprague-Dawley rats weighing approximately 300 g, were placed on an adenine diet for 21 non-consecutive days to induce kidney failure, followed by daily vitamin D3 (VitD3) injections for 4 sequential days to cause severe calcification throughout the cardiovascular system and kidneys. DiR-dye loaded and elastin antibody conjugated albumin nanoparticles were used to confirm the targeting of nanoparticles to the calcification area. The rats were divided into two groups for targeted removal of calcification starting at day 7 of the last doses of VitD3. The experimental group received biweekly IV injections of anti-elastin antibody conjugated EDTA loaded human serum albumin nanoparticles (EDTA-HSA-El-Ab NPs), while the sham controls received blank nanoparticles (Blank-HSA-El-Ab NPs) (5 injections in total). Micro-computed tomography (microCT) was used to analyze the extent of calcification. Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry studies were performed for osteogenic markers, including bone morphogenic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2), and tissue non-specific alkaline phosphatase (TNAP). For comparison, aortic ring organ cultures from healthy rats were treated with high phosphate to induce calcification in vitro, and then they were treated with EDTA. Human calcified femoral arteries were also treated ex vivo with EDTA-HSA-EL-Ab NPs to test if nanoparticles remove heavy calcification. EDTA-loaded nanoparticles that specifically target degraded elastin reversed existing heavy mineral deposits in arteries, as per elemental calcium analysis (124.161±34.410 µg Ca per mg of the dry aorta in Blank-HSA-El-Ab NPs vs. 100.520±19.131 µg in EDTA-HSA-El-Ab NPs group, P=0.04) and microCT (object volume, 129.001±37.785 vs. 29.815±24.169 mm3, P=0.0005). The reversal of aortic calcification was accompanied by a significant reduction of bone-associated mRNA expression of BMP2 and RUNX2 (P=0.01). Immunohistochemistry studies corroborated RT-PCR results, showing a reduction of BMP2 and RUNX2 stains in the vessel wall. The rat aortic ring culture study also showed similar results, where osteogenic genes (BMP2, RUNX2) and proteins (BMP2, RUNX2, TNAP) were suppressed upon reversal of calcification with EDTA (P=0.001). We also show ex vivo reversal of human femoral artery calcification by microCT (calcium intensity: untreated, 57.721±28.551 vs. day 6 of treatment, 5.441±3.615, P=0.01) by EDTA nanoparticle therapy. This is the first study showing the removal of calcium from heavily calcified arteries by using intravenous targeted EDTA therapy. Such therapy also reversed vascular smooth muscle cell osteoblastic transition and apoptosis in the arterial tissue, thereby potentially creating an environment for suitable tissue repair.

Exploring the therapeutic potential: Apelin-13's neuroprotective effects foster sustained functional motor recovery in a rat model of Huntington's disease.

Huntington's disease (HD) is a hereditary condition considered by the progressive degeneration of nerve cells in the brain, resultant in motor dysfunction and cognitive impairment. Despite current treatment modalities including pharmaceuticals and various therapies, a definitive cure remains elusive. Therefore, this study investigates the therapeutic potential effect of Apelin-13 in HD management. Thirty male Wistar rats were allocated into three groups: a control group, a group with HD, and a group with both HD and administered Apelin-13. Apelin-13 was administered continuously over a 28-day period at a dosage of around 30 mg/kg to mitigate inflammation in rats subjected to 3-NP injection within an experimental HD model. Behavioral tests, such as rotarod, electromyography (EMG), elevated plus maze, and open field assessments, demonstrated that Apelin-13 improved motor function and coordination in rats injected with 3-NP. Apelin-13 treatment significantly increased neuronal density and decreased glial cell counts compared to the control group. Immunohistochemistry analysis revealed reduced gliosis and expression of inflammatory factors in the treatment group. Moreover, Apelin-13 administration led to elevated levels of glutathione and reduced reactive oxygen species (ROS) level in the treated group. Apelin-13 demonstrates neuroprotective effects, leading to improved movement and reduced inflammatory and fibrotic factors in the HD model.

A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 μm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.

Chamuangone-rich rice bran oil ameliorates neurodegeneration in AlCl3/D-galactose model via modulation of behavioral, biochemical, and neurochemical parameters

Chamuangone is an exotic medicinal compound isolated from Garcinia cowa leaves. It shows great potential against inflammation, neurodegeneration, and oxidation. Through green extraction method, chamuangone-rich rice bran oil (CRBO) containing 1.97 mg/mL of chamuangone was obtained. This research study investigates the therapeutic effects of CRBO on D-galactose- and aluminum chloride (AlCl3)-induced Alzheimer’s disease in rat model. In all, 30 rats were divided into six groups and treated for 42 days as follows: control group (vehicle), disease control group (AlCl3 150 mg/kg + D-galactose 150 mg/kg p.o.), standard group (rivastigmine 3 mg/kg p.o.), and CRBO treatment groups with doses of 2.5, 5.0, and 7.5 mg/kg p.o. Neurobehavioral studies were performed on completion of 42 days. Furthermore, biochemical, neurochemical, and histopathological analyses were performed. CRBO treatment mitigated impairment in neuromuscular coordination, mentation and cognition in behavioral tasks. It potentially recovered (p &lt; 0.001) the declined level of catalase, superoxide dismutase, reduced glutathione and lipid peroxidation. Neurochemical analysis revealed the restoration of serotonin, noradrenaline, and dopamine concentration in the brain after CRBO treatment. Histopathological examination of vital organs revealed recovery in CRBO-treated rats in a dose-dependent manner. Owing to neurotoxic effects of inducing agents, the level of acetylcholinesterase decreased in disease control group; however, CRBO treatment recovered the declined activity of this enzyme. Therefore, it is concluded that CRBO significantly recovered the neurodegenerative effects through multiple pathways, such as amelioration of oxidative stress and neuronal plasticity. Therefore, this innovative green remedy can be considered as a natural alternative for treating neurodegenerative disorders.

Yigong San improves cognitive decline in a rat model of Alzheimer's disease by regulating intestinal microorganisms

To investigate the effect of Yigong San (YGS) on learning and memory abilities of rats with lipopolysaccharide (LPS)‑induced cognitive decline and explore its possible mechanism in light of intestinal microbiota. Forty SD rats were randomly divided into control group, model group, donepezil (1.3 mg/kg) group, and high-dose (5.25 g/kg) and low-dose (2.63 g/kg) YGS treatment groups. After 24 days of treatment with the corresponding drugs or water by gavage, the rats in the latter 4 groups received an intraperitoneal injection of LPS (0.5 mg/kg) to establish models of Alzheimer's disease (AD). Water maze test and HE staining were used to evaluate the changes in learning and memory abilities and pathomorphology of the hippocampus. The changes in gut microbial species of the rats were analyzed with 16S rRNA sequencing, and the levels of IL-6, TNF-α, and IL-1β in the brain tissue and serum were detected using ELISA. Compared with the AD model group, the YGS-treated rats showed significantly shortened escape latency on day 5 after modeling, reduced neuronal degeneration and necrosis in the hippocampus, lowered pathological score of cell damage, and decreased levels IL-6, TNF-α and IL-1β in the brain tissue and serum. The YGS-treated rats showed also obvious reduction of Alpha diversity indicators (ACE and Chao1) of intestinal microbiota with significantly increased abundance of Prevotellaceae species at the family level and decreased abundance of Desulfovibrionaceae, which were involved in such metabolic signaling pathways as cell community prokaryotes, membrane transport, and energy metabolism. YGS improves learning and memory abilities and hippocampal pathomorphology in AD rat models possibly by regulating the abundance of intestinal microbial species such as Prevotellaceae to affect the metabolic pathways for signal transduction, cofactors, and vitamin metabolism.

JWH133 attenuates behavior deficits and iron accumulation in 6-OHDA-induced Parkinson's disease model rats.

Growing evidence indicates that activation of cannabinoid type 2 (CB2) receptors protects dopamine neurons in the pathogenesis of Parkinson's disease (PD). However, the mechanisms underlying neuroprotection mediated by CB2 receptors are still elusive. In this study, we investigated the effects of CB2 receptor activation on 6-hydroxydopamine (6-OHDA)-induced dopamine neuron degeneration and iron accumulation in the substantia nigra (SN) of rats. We found that treatment with JWH133, a selective CB2 receptor agonist, significantly improved the apomorphine (APO)-induced rotational behavior in 6-OHDA-treated rats. The decreased numbers of tyrosine hydroxylase (TH)-positive neurons and reduced TH protein expression in the lesioned SN of rats were effectively restored by JWH133. Moreover, we found that JWH133 inhibited the increase of iron-staining cells in the lesioned SN of rats. To explore the protective mechanisms of activation of CB2 receptors on dopamine neurons, we further observed the effect of JWH133 on 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultured ventral mesencephalon (VM) neurons from rats. We found that JWH133 significantly inhibited the increase of intracellular reactive oxygen species (ROS), the activation of Caspase-3, the decrease of mitochondrial transmembrane potential (ΔΨm), and the decrease of Bcl-2/Bax protein expression caused by MPP+ treatment. JWH133 also inhibited the MPP+-induced upregulation of divalent metal transporter-1 (DMT1) and downregulation of ferroportin 1 (FPN1). Furthermore, JWH133 also suppressed the MPP+-accelerated iron influx in the VM neurons. These results suggest that activation of CB2 receptor suppresses MPP+-induced cellular iron accumulation and prevents neurodegeneration.NEW & NOTEWORTHY Expression of cannabinoid type 2 receptors (CB2Rs) was discovered on dopamine neurons in recent years. The role of CB2R expressed on dopamine neurons in the pathogenesis of Parkinson's disease (PD) has not been fully elucidated. The content of iron accumulation in the brain is closely related to the progress of PD. We verified the inhibitory effect of CB2R on iron deposition in dopamine neurons through experiments, which provided a new idea for the treatment of PD.

Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer's-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function.

Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.

Are the promnestic effects of neurokinin 3 receptor mediated by hippocampal neurogenesis in a Aβ-induced rat model of Alzheimer's disease?

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by cognitive dysfunction, memory loss and mood changes. Hippocampal neurogenesis has been suggested to play a role in learning and memory. Neurokinin 3 receptor (NK3R) has been shown to be prevalent in the hippocampus region. The aim of the project was to investigate the role of hippocampal neurogenesis in the promnestic effects of NK3R agonist administration in an amyloid beta-induced AD rat model. Wistar albino rats were divided into control, Alzheimer, NK3R agonist and Alzheimer + NK3R agonist groups. The open field (OF) test and Morris water maze (MWM) test were performed for locomotor activity and memory analysis. Peptide gene expression levels (Nestin, DCX, Neuritin, MASH1, Neun, BDNF) were analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR). In the OF test, the group-time relationship was found to be statistically different in the parameters of distance travelled and percentage of movement (p< 0.05). In MWM, the time to reach the platform and the time spent in the target quadrant were statistically significant between the groups (p< 0.05). Statistically significant differences were observed in gene expression levels (Nestin, DCX, Neuritin, MASH1) in the hippocampal tissue of rats between the groups (p< 0.05). NK3 receptor agonism favourably affected hippocampal neurogenesis in AD model rats. It was concluded that NK3 receptor agonism in the hippocampus, which is the first affected region in the physiopathology of AD, may be effective in both the formation of neural precursor cells and the reduction of neuronal degeneration. The positive effect of NK3R on cognitive functions may be mediated by hippocampal neurogenesis.

Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.

The ANGPTL4-HIF-1α loop: a critical regulator of renal interstitial fibrosis

BackgroundRenal interstitial fibrosis (RIF) is a progressive, irreversible terminal kidney disease with a poor prognosis and high mortality. Angiopoietin-like 4 (ANGPTL4) is known to be associated with fibrosis in various organs, but its impact on the RIF process remains unclear. This study aimed to elucidate the role and underlying mechanisms of ANGPTL4 in the progression of RIF.MethodsIn vivo, a chronic kidney disease (CKD) rat model of renal interstitial fibrosis was established via intragastric administration of adenine at different time points (4 and 6 weeks). Blood and urine samples were collected to assess renal function and 24-h urinary protein levels. Kidney tissues were subjected to HE and Masson staining for pathological observation. Immunohistochemistry and real-time quantitative PCR (qRT‒PCR) were performed to evaluate the expression of ANGPTL4 and hypoxia-inducible factor-1α (HIF-1α), followed by Pearson correlation analysis. Subsequently, kidney biopsy tissues from 11 CKD patients (6 with RIF and 5 without RIF) were subjected to immunohistochemical staining to validate the expression of ANGPTL4. In vitro, a fibrosis model of human renal tubular epithelial cells (HK2) was established through hypoxic stimulation. Subsequently, an HIF-1α inhibitor (2-MeOE2) was used, and ANGPTL4 was manipulated using siRNA or plasmid overexpression. Changes in ANGPTL4 and fibrosis markers were analyzed through Western blotting, qRT‒PCR, and immunofluorescence.ResultsANGPTL4 was significantly upregulated in the CKD rat model and was significantly positively correlated with renal injury markers, the fibrotic area, and HIF-1α. These results were confirmed by clinical samples, which showed a significant increase in the expression level of ANGPTL4 in CKD patients with RIF, which was positively correlated with HIF-1α. Further in vitro studies indicated that the expression of ANGPTL4 is regulated by HIF-1α, which in turn is subject to negative feedback regulation by ANGPTL4. Moreover, modulation of ANGPTL4 expression influences the progression of fibrosis in HK2 cells.ConclusionOur findings indicate that ANGPTL4 is a key regulatory factor in renal fibrosis, forming a loop with HIF-1α, potentially serving as a novel therapeutic target for RIF.

Effect of imipramine on memory, adult neurogenesis, neuroinflammation, and mitochondrial biogenesis in a rat model of alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory loss. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and antioxidant properties in the central nervous system. The aim of this study was to investigate the neuroprotective effects of imipramine on streptozotocin (STZ)-induced memory impairment. Male Wistar rats received an intracerebroventricular injection of STZ (3 mg/kg, 3 μl/ventricle) using the stereotaxic apparatus. The Morris water maze and passive avoidance tests were used to evaluate cognitive functions. 24 h after the STZ injection, imipramine was administered intraperitoneally at doses of 10 or 20 mg/kg for 14 consecutive days. The mRNA and protein levels of neurotrophic factors (BDNF and GDNF) and pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) were measured in the hippocampus using real-time PCR and ELISA techniques, respectively. In addition, real-time PCR was used to evaluate the mRNA levels of markers associated with neurogenesis (Nestin, DCX, and Ki67) and mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM). The results showed that imipramine, especially at a dose of 20 mg/kg, effectively improved STZ-induced memory impairment. This improvement was associated with an increase in neurogenesis and neurotrophic factors and a decrease in neuroinflammation and mitochondrial biogenesis dysfunction. Based on these results, imipramine appears to be a promising therapeutic option for improving cognitive functions in neurodegenerative diseases such as AD.

Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer's disease

Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aβ25–35 had impaired spatial learning and memory, which was accompanied by higher levels of Aβ plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aβ25–35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.

Repurposing ezetimibe as a neuroprotective agent in a rotenone-induced Parkinson’s disease model in rats: Role of AMPK/SIRT-1/PGC-1α signaling and autophagy

As a severe neurological disorder, Parkinson’s disease (PD) is distinguished by dopaminergic neuronal degeneration in the substantia nigra (SN), culminating in motor impairments. Several studies have shown that activation of the AMPK/SIRT1/PGC1α pathway contributes to an increase in mitochondrial biogenesis and is a promising candidate for the management of PD. Furthermore, turning on the AMPK/SIRT1/PGC1α pathway causes autophagy activation, which is fundamental for maintaining neuronal homeostasis. Interestingly, ezetimibe is an antihyperlipidemic agent that was recently reported to possess pleiotropic properties in neurology by triggering the phosphorylation and activation of AMPK. Thus, our study aimed to investigate the neuroprotective potential of ezetimibe in rats with rotenone-induced PD by activating AMPK. Adult male Wistar rats received rotenone (1.5 mg/kg, s.c.) every other day for 21 days to induce experimental PD. Rats were treated with ezetimibe (5 mg/kg/day, i.p.) 1 h before rotenone. Ezetimibe ameliorated the motor impairments in open field, rotarod and grip strength tests, restored striatal dopamine and tyrosine hydroxylase in the SN, up-regulated p-AMPK, SIRT1, and PGC1α striatal expression, upsurged the expression of ULK1, beclin1, and LC3II/I, reduced Bax/Bcl2 ratio, and alleviated rotenone-induced histopathological changes in striatum and SN. Our findings also verified the contribution of AMPK activation to the neuroprotective effect of ezetimibe by using the AMPK inhibitor dorsomorphin. Together, this work revealed that ezetimibe exerts a neuroprotective impact in rotenone-induced PD by activating AMPK/SIRT-1/PGC-1α signaling, enhancing autophagy, and attenuating apoptosis. Thus, ezetimibe’s activation of AMPK could hold significant therapeutic promise for PD management.

The Protective Effect of Uridine in a Rotenone-Induced Model of Parkinson's Disease: The Role of the Mitochondrial ATP-Dependent Potassium Channel.

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.

Subzero project: comparing trace element profiles of enriched mitochondria fractions from frozen and fresh liver tissue

From organs to subcellular organelles, trace element (TE) homeostasis is fundamental for many physiological processes. While often overlooked in early stages, manifested TE disbalance can have severe health consequences, particularly in the context of aging or pathological conditions. Monitoring TE concentrations at the mitochondrial level could identify organelle-specific imbalances, contributing to targeted diagnostics and a healthier aging process. However, mitochondria isolation from frozen tissue is challenging, as it poses the risk of TE losses from the organelles due to cryodamage, but would significantly ease routine laboratory work. To address this, a novel method to isolate an enriched mitochondria fraction (EMF) from frozen tissue was adapted from already established protocols. Validation of manganese (Mn), iron (Fe), and copper (Cu) quantification via inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) showed sufficiently low quantification limits for EMF TE analysis. Successful mitochondrial enrichment from frozen liver samples was confirmed via immunoblots and transmission electron microscopy (TEM) revealed sufficient structural integrity of the EMFs. No significant differences in EMF TEs between frozen and fresh tissue were evident for Mn and Cu and only slight decreases in EMF Fe. Consequently, EMF TEs were highly comparable for isolates from both tissue states. In application, this method effectively detected dietary differences in EMF Fe of a murine feeding study and identified the disease status in a Wilson disease rat model based on drastically increased EMF Cu. In summary, the present method is suitable for future applications, facilitating sample storage and high-throughput analyses of mitochondrial TEs.Graphical abstract

Oral administration of encapsulated catechin in chitosan-alginate nanoparticles improves cognitive function and neurodegeneration in an aluminum chloride-induced rat model of Alzheimer's disease.

The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl3)-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl3 treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl3 + Catechin), and treatment group 2 (AlCl3 + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl3 induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl3 was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats.

Dietary Fiber Fermentability and Viscosity Impact Phosphorus Homeostasis and Urinary Phosphorus Excretion in a Rat Model of Chronic Kidney Disease

Dietary Fiber Fermentability and Viscosity Impact Phosphorus Homeostasis and Urinary Phosphorus Excretion in a Rat Model of Chronic Kidney Disease