Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats

Objective(s): Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress. Materials and Methods: Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single ICV injection (10 μl) of fresh mitochondria isolated from the brain of young rats for five minutes (2 µl/min). Finally, the levels of Malondialdehyde (MDA), Cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC.Results: Young mitochondria administration reduced neuronal apoptosis in the PFC, associated with down-regulation of MDA, Bax, and Caspase-3 and up-regulation of Bcl-2. Moreover, fresh mitochondria partially improved the chronic stress-induced mitochondrial dysfunction in aged rats, as indicated by reduced cytochrome c (Cyt c) release from the mitochondria.Conclusion: These results suggest mitotherapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli

Troxerutin protects hippocampal neurons against amyloid beta-induced oxidative stress and apoptosis

Alzheimer’s disease (AD) is an age-related neurodegenerative disease linked with increased production and/or deposition of amyloid-beta (Aβ) in the brain. The aim of the present study was to investigate the possible neuroprotective effect of troxerutin on an animal model of Alzheimer's disease. Alzheimer model was induced by a single dose intracerebroventricular (ICV) injection of Aβ 1–42 (5 nmol/5 μl). Thereafter, troxerutin (300 mg/kg) was gavaged for 14 days. The hippocampal malondialdehyde (MDA) levels and enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and acetylcholinesterase (AChE) were measured using enzymelinked immunosorbent assay (ELISA) method. In addition, the number of apoptotic cells in the dentate gyrus (DG) was assessed by TUNEL kit. The results showed that ICV microinjection of Aβ 1-42 increased MDA levels, reduced SOD and GPx, and increased AChE activities in the hippocampus. Chronic administration of troxerutin significantly attenuated MDA levels and AChE activity and increased SOD and GPx activities in the hippocampus. Moreover, the number of apoptotic cells was decreased by troxerutin treatment. Taken together, our study demonstrated that troxerutin could increase the resistance of hippocampal neurons against apoptosis, at least in part, by diminishing the activity of AChE and oxidative stress. Therefore, troxerutin may have beneficial effects in the management of Alzheimer's disease

Effects of troxerutin on anxiety- and depressive-like behaviors induced by chronic mild stress in adult male rats

Objective(s):Chronic stress has been linked to the pathophysiology of mood disorders including anxiety and depression. In this study, we aimed to investigate the effect of troxerutin (TRX), as a flavonol, on stress-induced anxiety and depression.Materials and Methods: 56 animals were randomly divided into seven groups (n=8 per group) as follows: control, saline, TRX 50, TRX 150, TRX 300, Diazepam, and Imipramine. Chronic mild stress (CMS) was induced by restraining animals in Plexiglas cylinders for 1 hr each day for 25 consecutive days. Different doses (50, 150, and 300 mg/kg, oral gavage) of troxerutin was gavaged for 14 consecutive days. At the end of treatments, anxiety- and depressive-like behaviors were tested using elevated plus-maze (EPM), open field test (OFT), and forced swimming test (FST). Results: CMS significantly increased immobility (

Serotonergic system modulation holds promise for L‐DOPA‐induced dyskinesias in hemiparkinsonian rats

The alleged effects of serotonergic agents in alleviating levodopa-induced dyskinesias (LIDs) in parkinsonian patients are debatable. To this end, we systematically reviewed the serotonergic agents used for the treatment of LIDs in a 6-hydroxydopamine model of Parkinson’s disease in rats. We searched MEDLINE via PubMed, Embase, Google Scholar, and Proquest for entries no later than March 2018, and restricted the search to publications on serotonergic agents used for the treatment of LIDs in hemiparkinsonian rats. The initial search yielded 447 citations, of which 49 articles and one conference paper met our inclusion criteria. The results revealed ten different categories of serotonergic agents, including but not limited to 5-HT1A/BR agonists, 5-HT2AR antagonists, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRIs), and tricyclic antidepressants (TCAs), all of which improved LIDs without imposing considerable adverse effects. Although there is promising evidence regarding the role of these agents in relieving LIDs in hemiparkinsonian rats, further studies are needed for the enlightenment of hidden aspect of these molecules in terms of mechanisms and outcomes. Given this, improving the quality of the pre-clinical studies and designing appropriate clinical trials will help fill the bench-to-bedside gap

Testosterone May Hold Therapeutic Promise for the Treatment ofIschemic Stroke in Aging: A Closer Look at Laboratory Findings

Male sex is more prone to cerebrovascular disorders, yet the exact role of androgens in cerebralischemia remains unclear. Here we reviewed current understanding of testosterone (TES)neuroprotective activity against ischemic stroke and mechanisms underlying these effects inaging. TES may exert a neuroprotective effect in aging through pathways including inhibition ofoxidant molecules production, enhancing the enzymatic antioxidant capacity of the brain andmodulation of apoptotic cell death. Given this, a better understanding of the neuroprotectiveroles of TES may propose an effective therapeutic strategy to improve the quality of life anddecrease androgen-related cerebrovascular problems in the aging men

Protective effects of troxerutin on maternal high-fat diet-induced impairments of spatial memory and apelin in the male offspring

Objective(s): Maternal high-fat diet (HFD) is linked with metabolic and cognitive deficits in offspring. Neuroprotective effects of troxerutin, a natural bioflavonoid, have been reported recently. This study aimed to investigate the effects of troxerutin on spatial memory and serum and hippocampal apelin levels in the male offspring of HFD fed mothers.Materials and Methods: Three-week-old female Wistar rats (n= 40) received HFD or control diet (CD) for 8 weeks. After mating, pregnant animals were divided into two subgroups according to the troxerutin (TRO) supplementation: CD, CD+TRO, HFD, and HFD+TRO. HFD continued to the end of lactation in HFD and HFD+TRO groups. TRO was gavaged (150 mg/kg/day) during pregnancy. After weaning, the male offspring were fed a normal diet until 12 weeks of age. Spatial memory was evaluated in the Morris water maze (MWM) on postnatal day (PND) 90. Total apelin concentration was measured in the serum of maternal rats before mating and after lactation and also in the serum and hippocampus of their male offspring.Results: Both traveled distance (

Effect of troxerutin on apelin-13, apelin receptors (APJ), and ovarian histological changes in the offspring of high-fat diet fed rats

Objective(s): Maternal high-fat diet (HFD) consumption has been linked to metabolic disorders and reproductive dysfunctions in offspring. Troxerutin (TRO) has anti-hyperlipidemic, anti-oxidant, and anti-inflammatory effects. This study examined the effects of TRO on apelin-13, its receptors mRNA and ovarian histological changes in the offspring of HFD fed rats. Materials and Methods: Female Wistar rats were randomly divided into control diet (CD) or HFD groups and received these diets for eight weeks. After mating, dams were assigned into four subgroups: CD, CD + TRO, HFD, and HFD + TRO, and received their respective diets until the end of lactation. Troxerutin (150 mg/kg/day) was gavaged in the CD + TRO and HFD + TRO groups during pregnancy. On the postnatal day (PND) 21 all female offspring were separated and fed CD until PND 90. On PND 90 animals were sacrificed and ovarian tissue samples were collected for further evaluation. Results: Results showed that HFD significantly decreased serum apelin-13 in the female offspring of the HFD dams, which was significantly reversed by TRO. Moreover, real-time polymerase chain reaction (PCR) analysis revealed that TRO treatment significantly decreased the ovarian mRNA expression of the apelin-13 receptor in the troxerutin-received offspring. Furthermore, histological examination revealed that TRO increased the number of atretic follicles in the ovaries of HFD+TRO offspring.Conclusion: Maternal high fat feeding compromises ovarian health including follicular growth and development in the adult offspring and troxerutin treatment improved negative effects of maternal HFD on the apelin-13 level and ovarian development of offspring

Nicotine Modulates Cognitive Function in D-Galactose-Induced Senescence in Mice

Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs