AMPK Signaling Pathway as a Potential Therapeutic Target for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the loss of dopaminergic neurons. Genetic factors, inflammatory responses, oxidative stress, metabolic disorders, cytotoxic factors, and mitochondrial dysfunction are all involved in neuronal death in neurodegenerative diseases. The risk of PD can be higher in aging individuals due to decreased mitochondrial function, energy metabolism, and AMP-activated protein kinase (AMPK) function. The potential of AMPK to regulate neurodegenerative disorders lies in its ability to enhance antioxidant capacity, reduce oxidative stress, improve mitochondrial function, decrease mitophagy and macroautophagy, and inhibit inflammation. In addition, it has been shown that modulating the catalytic activity of AMPK can protect the nervous system. This article reviews the mechanisms by which AMPK activation can modulate PD.

Photobiomodulation combination therapy as a new insight in neurological disorders: a comprehensive systematic review.

Preclinical and clinical studies have indicated that combining photobiomodulation (PBM) therapy with other therapeutic approaches may influence the treatment process in a variety of disorders. The purpose of this systematic review was to determine whether PBM-combined therapy provides additional benefits over monotherapies in neurologic and neuropsychiatric disorders. In addition, the review describes the most commonly used methods and PBM parameters in these conjunctional approaches.To accomplish this, a systematic search was conducted in Google Scholar, PubMed, and Scopus databases through January 2024. 95 potentially eligible articles on PBM-combined treatment strategies for neurological and neuropsychological disorders were identified, including 29 preclinical studies and 66 clinical trials.According to the findings, seven major categories of studies were identified based on disease type: neuropsychiatric diseases, neurodegenerative diseases, ischemia, nerve injury, pain, paresis, and neuropathy. These studies looked at the effects of laser therapy in combination with other therapies like pharmacotherapies, physical therapies, exercises, stem cells, and experimental materials on neurological disorders in both animal models and humans. The findings suggested that most combination therapies could produce synergistic effects, leading to better outcomes for treating neurologic and psychiatric disorders and relieving symptoms.These findings indicate that the combination of PBM may be a useful adjunct to conventional and experimental treatments for a variety of neurological and psychological disorders.

Exercise and insulin glargine administration in mothers with diabetes during pregnancy ameliorate function of testis in offspring: Consequences on apelin-13 and its receptor.

AIMS: Despite the evidence exhibited that diabetes during gestation (DDG) is linked with reproductive dysfunction in offspring, the underlying cellular mechanisms involved are not precisely defined. This study was designed to assess the impact of voluntary exercise and insulin glargine on DDG-induced metabolic and reproductive disorders in male offspring. MAIN METHODS: Fifty female Wistar rats (three weeks old) received a control diet (n = 10) or high-fat-high-sucrose diet (to induce DDG; n = 40) for six weeks before breeding. From the 7th day of pregnancy onwards, blood glucose over 140 mg/dL was characterized as DDG. Then, the DDG animals were randomly divided into four subgroups with/without voluntary exercise and/or insulin glargine. To evaluate insulin resistance, a glucose tolerance test was performed on the 15th day of pregnancy. After three weeks, male offspring were weaned, and fed a control diet until 12 weeks old. At the end of the experiment, the lipid profile, sex hormones, and apelin-13 in the serum, mRNA expression of apelin receptors (APJ) in the testis and sperm analysis were assessed. KEY FINDINGS: Our results indicated that voluntary exercise and/or insulin glargine administration in mothers with DDG ameliorated lipid profile, and sex hormones alterations, reduced the serum level of apelin-13, as well as increased APJ expression in testis, and quality of sperm in offspring. SIGNIFICANCE: Combined administration of voluntary exercise and insulin glargine during pregnancy by regulating of apelinergic system and inhibiting the metabolic and reproductive complications induced by DDG, can be considered as a suitable therapeutic strategy for improving sub-or in-fertility in the male offspring.

Chronic stress-induced anxiety-like behavior, hippocampal oxidative, and endoplasmic reticulum stress are reversed by young plasma transfusion in aged adult rats.

Objectives: Aging and stress synergistically induce behavioral dysfunctions associated with oxidative and endoplasmic reticulum (ER) stress in brain regions. Considering the rejuvenating effects of young plasma on aging brain function, in the current study, we examined the effects of young plasma administration on anxiety-like behavior, NADH oxidase, NADPH oxidase, and ER stress markers in the hippocampus of old male rats. Materials and Methods: Young (3 months old) and aged (22 months old) rats were randomly assigned into five groups: young control (Y), aged control (A), aged rats subjected to chronic stress for four weeks (A+S), aged rats subjected to chronic stress and treated with old plasma (A+S+OP), and aged rats subjected to chronic stress and treated with young plasma (A+S+YP). Systemic injection of (1 ml) young and old plasma was performed for four weeks (3 times/week). Results: Young plasma transfusion significantly improved anxiety-like behavior in aged rats and modulated oxidative stress in the hippocampus, evidenced by the increased NADH oxidase (NOX) activity and the reduced NADPH oxidase. In addition, the levels of C/EBP homologous protein (CHOP) and Glucose-Regulated Protein 78 (GRP-78), as ER stress markers, markedly reduced in the hippocampus following the administration of young plasma. Conclusion: These findings suggest that young plasma transfusion could reverse anxiety-like behavior in stress-exposed aged rats by modulating the hippocampal oxidative and ER stress markers.

Sericin Improves Memory Impairment Via Activation of the PKA-CREB-BDNF Signaling Pathway and Suppression of Oxidative Stress in Ovariectomized Mice.

Menopause results in estrogen hormone deficiency which causes changes in brain morphology and cognitive impairments. The risk of breast and ovarian cancer increases with estrogen therapy. Thus, finding a substitute treatment option for women in menopause is necessary. In the current study, the impact of chronic sericin treatment (200 mg/kg/day for 6 weeks, gavage) on memory process, oxidative stress markers, synaptic neurotransmission, and acetylcholinesterase (AChE) activity in the hippocampus (HIP) of ovariectomized (OVX) mice was examined and compared to the effects of 17ß-estradiol (Es; 20 µg/kg, s.c.). The results demonstrated that sericin and Es administration improved spatial and recognition memory of the OVX animals in the both Lashley III maze and novel object recognition tests. Moreover, sericin-treated OVX mice showed decreased ROS levels, increased endogenous antioxidant defense capacity, and decreased AChE activity in the HIP. Additionally, sericin and Es therapy up-regulated pre-and-post-synaptic protein markers and increased BDNF, CREB, and protein kinase A (PKA) protein expressions in the HIP of OVX mice. Overall, the activation of the PKA-CREB-BDNF signaling pathway by sericin can provide protection against OVX-induced cognitive dysfunction, making it a potential alternative for managing cognitive deficits in postmenopausal women.

Transcranial photobiomodulation mitigates learning and memory impairments induced by hindlimb unloading in a mouse model of microgravity exposure by suppression of oxidative stress and neuroinflammation signaling pathways.

Prolonged microgravity exposure causes cognitive impairment. Evidence shows that oxidative stress and neuroinflammation are involved in the causation. Here, we explore the effectiveness of transcranial near-infrared photobiomodulation (PBM) on cognitive deficits in a mouse model of simulated microgravity. 24 adult male C57BL/6 mice were assigned into three groups (8 in each); control, hindlimb unloading (HU), and HU + PBM groups. After surgery to fit the suspension fixing, the animals were housed either in HU cages or in their normal cage for 14 days. The mice in the HU + PBM group received PBM (810 nm laser, 10 Hz, 8 J/cm2) once per day for 14 days. Spatial learning and memory were assessed in the Lashley III maze and hippocampus tissue samples were collected to assess oxidative stress markers and protein expression of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2), Sirtuin 1 (Sirt1), and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Behavioral testing showed that the PBM-treated animals had a shorter latency time to find the target and fewer errors than the HU group. PBM decreased hippocampal lipid peroxidation while increasing antioxidant defense systems (glutathione peroxidase, superoxide dismutase, and total antioxidant capacity) compared to HU mice. PBM increased protein expression of Sirt1, Nrf2, and BDNF while decreasing NF-κB compared to HU mice. Our findings suggested that the protective effect of PBM against HU-induced cognitive impairment involved the activation of the Sirt1/Nrf2 signaling pathway, up-regulation of BDNF, and reduction of neuroinflammation and oxidative stress in the hippocampus.

Sericin improves memory and sociability impairments evoked by transient global cerebral ischemia through suppression of hippocampal oxidative stress, inflammation, and apoptosis.

Sericin (Ser) is a natural neuroactive macromolecule with diverse pharmacological properties, and our previous findings have shown its neuroprotective potentials. This study aimed to investigate the therapeutic potential of Ser on cognitive dysfunction induced by transient global cerebral ischemia/reperfusion (tGI/R) and its mechanism of action. The tGI/R was induced in BALB/c mice by bilateral occlusion of the common carotid arteries for two 5 min followed by a 10-min reperfusion period. After 24 h, mice were treated with normal saline or different doses of Ser (100, 200, and 300 mg/kg) for 10 days. Cognitive performances were assessed using the Barnes maze and social interaction tasks. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) as well as pro-inflammatory cytokines (interleukin (IL)-6 and tumor necrosis factor-alpha) and anti-inflammatory cytokine (IL-10) were assessed in the hippocampus. Markers of apoptosis (pro- and cleaved caspase-9 and 3, Bax, and Bcl-2) were assessed by Western blotting. Besides, transferase-mediated dUTP nick end-labeling assay was used to detect apoptotic cell death. We show here that Ser administration improved tGI/R-induced cognitive deficits, enhanced the activity of SOD and GPx, increased TAC levels, while reduced MDA levels. Notably, Ser decreased neuronal apoptotic cell death in the hippocampal dentate gyrus (DG) region, accompanied by suppression of neuroinflammation, downregulation of pro-apoptotic proteins (caspase-9, caspases-3, and Bax), and upregulation of anti-apoptotic protein, Bcl-2. Taken together, Ser administration protected hippocampal neurons from apoptotic cell death by impeding oxidative stress and inflammatory responses and, in turn, improved cognitive function in the tGI/R mice.

The role of apelinergic system in metabolism and reproductive system in normal and pathological conditions: an overview.

Lifestyle changes have made metabolic disorders as one of the major threats to life. Growing evidence demonstrates that obesity and diabetes disrupt the reproductive system by affecting the gonads and the hypothalamus-pituitary-gonadal (HPG) axis. Apelin, an adipocytokine, and its receptor (APJ) are broadly expressed in the hypothalamus nuclei, such as paraventricular and supraoptic, where gonadotropin-releasing hormone (GnRH) is released, and all three lobes of the pituitary, indicating that apelin is involved in the control of reproductive function. Moreover, apelin affects food intake, insulin sensitivity, fluid homeostasis, and glucose and lipid metabolisms. This review outlined the physiological effects of the apelinergic system, the relationship between apelin and metabolic disorders such as diabetes and obesity, as well as the effect of apelin on the reproductive system in both gender. The apelin-APJ system can be considered a potential therapeutic target in the management of obesity-associated metabolic dysfunction and reproductive disorders.

Insulin resistance is associated with cognitive dysfunction in multiple sclerosis patients: A cross-sectional study.

Multiple sclerosis (MS) is a progressive inflammatory neurodegenerative disease of the nervous system accompanied by demyelination. MS-associated cognitive impairments mainly involve recent memory, information processing speed, stable memory, and executive function. Moreover, MS is associated with impaired glucose and insulin metabolism, which can exacerbate cognitive decline. The present study aimed to compare the cognitive status of MS patients with and without insulin resistance. In this cross-sectional study, 74 relapsing-remitting multiple sclerosis diagnosed patients were enrolled. Indicators of insulin resistance, including fasting blood glucose, insulin level, and homeostatic model assessment of insulin resistance (HOMA-IR) index, were measured. They were then divided into two groups based on the results of the HOMA-IR index. Cognition status was evaluated by the minimal assessment of cognitive function in multiple sclerosis battery. The prevalence of insulin resistance was 37.8%, and the prevalence of cognitive decline was estimated to be 67.56%. Mean scores of the California verbal learning test (CVLT), CVLT delayed free recall, controlled oral word association test, and judgment of line orientation tests were significantly lower in MS patients with insulin resistance than without. In addition, a negative correlation was demonstrated between the results of the CVLT, CVLT delayed free recall, controlled oral word association test, judgment of line orientation tests, brief visuospatial memory test, and Delis-Kaplan executive function system sorting tests and fasting insulin levels. Greater verbal memory and spatial comprehension impairments were observed in MS patients with insulin resistance.

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

Objectives: 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.

Synergistic effects of combined therapy with cerebrolysin and enriched environment on anxiety-like behavior and spatial cognitive deficits in posttraumatic stress disorder-like mouse model.

Posttraumatic stress disorder (PTSD) is a serious neuropsychiatric disorder that occurs after exposure to stressful, fearful, or troubling events. Cerebrolysin (CBL), consists of low molecular weights neurotrophic factors and amino acids obtained from purified porcine brain proteins. This study aimed to evaluate the possible therapeutic effects of enriched environment (EE) and CBL alone or combined for reducing anxiety and cognitive deficits in PTSD-like mouse models. For this purpose, inescapable electric foot shocks were delivered to Balb/c mice for two consecutive days. Then mice were treated with CBL (2.5 mL/kg) and/or were kept in EE (2 h per day) or received their combination for 14 consecutive days. The hole-board test and Lashley III paradigm were used to assess anxiety and spatial learning and memory, respectively. Changes in the serum corticosterone level and expression of synaptic elements, including; growth-associated protein 43, post-synaptic density 95, and synaptophysin were assessed in the hippocampus. This model caused anxiety and spatial memory impairment associated with increased serum corticosterone levels and decreased synaptic elements. Nevertheless, CBL and/or combination treatment could reverse behavioral and molecular alterations. Our findings indicated that CBL, separately or in combination with EE, is effective in reducing anxiety and spatial memory impairment in PTSD-like mice.

Mitotherapy restores hippocampal mitochondrial function and cognitive impairment in aged male rats subjected to chronic mild stress.

This study aimed to determine the effects of mitotherapy on learning and memory and hippocampal kynurenine (Kyn) pathway, mitochondria function, and dendritic arborization and spines density in aged rats subjected to chronic mild stress. Twenty-eight male Wistar rats (22 months old( were randomly divided into Aged, Aged + Mit, Aged + Stress, and Aged + Stress + Mit groups. Aged rats in the stress groups were subjected to different stressors for 28 days. The Aged + Mit and Aged + stress + Mit groups were treated with intracerebroventricular injection (10 µl) of fresh mitochondria harvested from the young rats' brains, and other groups received 10 µl mitochondria storage buffer. Spatial and episodic-like memories were assessed via the Barnes maze and novel object recognition tests. Indoleamine 2,3-dioxygenase (IDO) expression and activity, Kyn, Tryptophan (TRY), ATP levels, and mitochondrial membrane potential (MMP) were measured in the hippocampus region. Golgi-Cox staining was also performed to assess the dendritic branching pattern and dendritic spines in the hippocampal CA1 subfield. The results showed that mitotherapy markedly improved both spatial and episodic memories in the Aged + Stress + Mit group compared to the Aged + Stress. Moreover, mitotherapy decreased IDO protein expression and activity and Kyn levels, while it increased ATP levels and improved MMP in the hippocampus of the Aged + Stress + Mit group. Besides, mitotherapy restored dendritic atrophy and loss of spine density in the hippocampal neurons of the stress-exposed aged rats. These findings provide evidence for the therapeutic effect of mitotherapy against stress-induced cognitive deterioration in aged rats by improving hippocampal mitochondrial function and modulation of the Kyn pathway.

Maternal vitamin D supplementation and treadmill exercise attenuated vitamin D deficiency-induced anxiety-and depressive-like behaviors in adult male offspring rats.

BACKGROUND: Vitamin D is a vital neuroactive steroid for brain development and function. Vitamin D deficiency is a worldwide health problem, particularly in children and women. Gestational or developmental vitamin D deficiency is associated with an increased risk of neurodevelopmental and neuropsychiatric disorders. This study examined the effect of maternal vitamin D dietary manipulations and treadmill exercise on anxiety-and depressive-related behaviors, pro-inflammatory cytokines, and prefrontal cortex (PFC) protein levels of brain-derived neurotrophic factor (BDNF) and vitamin D receptor (VDR) in adult male offspring born to vitamin D-deficient diet (VDD)-fed dams. METHODS AND RESULTS: Female rats were provided standard diet (SD) or VDD for six weeks and then were treated with SD (started a week before mating throughout gestation and lactation) and treadmill exercise (a week before mating until gestational day 20). Male offspring were separated on postnatal day (PND) 21 and fed SD chow until PND90. Our results demonstrated that maternal vitamin D deficiency increased anxiety and depression-related behaviors, increased levels of TNF-α and IL-1ß in serum, and decreased prefrontal protein expressions of BDNF and VDR in adult male offspring. However, maternal vitamin D supplementation and treadmill exercise reversed these changes alone or in combination. CONCLUSION: It seems that developmental vitamin D deficiency disrupts brain development and has a long-lasting effect on VDR and BDNF signaling in the rat brain resulting in neuropsychiatric disorders in offspring. Therefore, vitamin D supplementation and physical exercise are reasonable strategies to prevent these neurobehavioral impairments.

Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson's disease.

PURPOSE: Parkinson's disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood-brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats. METHODS: Wistar rats were randomly divided into sham, PD, PD + levodopa and PD + HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and confirmed by rotation and the Murprogo's tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.) were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels and α-synuclein protein expression in the SN were also measured. RESULTS: The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. In addition, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity. CONCLUSION: According to the results, HCQ has a beneficial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.

Effect of intranasal administration of caffeine on mPFC ischemia­induced cognitive impairment in BALB/c mice.

Caffeine is a psychoactive compound used widely to enhance cognitive functions in human or animal studies. The present study examined the effects of caffeine on cognitive performance and inflammatory factors in mice with medial prefrontal cortex (mPFC) ischemia. Mice underwent a photothrombotic mPFC ischemic stroke and were treated with normal saline or caffeine at different doses intranasally for 7 days. The sham surgery animals received normal saline intranasally. The Morris water maze test and social interaction test were performed to assess spatial and social memories, respectively. In addition, the levels of inflammatory proteins, including tumor necrosis factor­alpha, interleukin­6, and interleukin­10, were measured in the mPFC using immunoblotting. The results showed that mPFC ischemia impaired spatial memory and social behaviors, and caffeine at doses of 0.05 and 0.1 mg improved behavioral outcomes in the ischemic groups. Also, caffeine reversed ischemia­induced high levels of pro­inflammatory biomarkers and enhanced the expression of the anti­inflammatory mediator. Our findings indicate that caffeine alleviated mPFC ischemia­induced memory disturbances, probably through the modulation of the inflammatory mediators.

Coenzyme Q10 ameliorates aging-induced memory deficits via modulation of apoptosis, oxidative stress, and mitophagy in aged rats.

The behavioral effects and molecular signaling mechanisms of Coenzyme Q10 (Q10) in age-related memory impairment are poorly understood. This study aimed to investigate the effects of Q10 on memory impairment, oxidative stress, apoptosis, and mitophagy in aged rats. 40 aged (24 months old) and 10 young (3 months old) male Wistar rats were randomly divided into the following groups (n = 10/group): young + vehicle, aged + vehicle, and aged + Q10 (at 100, 200, 300 mg/kg/day doses). Treatments were administrated orally by gavage for 2 weeks. The novel object recognition test was used to assess episodic memory. Oxidative stress, apoptosis, and mitophagy-related protein expressions were measured in the hippocampus. We found that Q10 reversed aging-induced memory impairment at the dose of 300 mg/kg. Moreover, aging was associated with a reduction in ATP production, decrease in mitophagy-related proteins (PINK, Parkin, and P62 levels and LC3II/I ratio), excessive generation of reactive oxygen species and lipid peroxidation, and apoptosis in the hippocampus, which were partially reversed following oral administration of Q10. These findings indicate the therapeutic potential of Q10 in aging-induced memory decline.

Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in Poststroke Depression: A Systematic Review and Meta-Analysis.

Objectives: Evidence shows that stroke-induced inflammatory responses play an essential role in the development of poststroke depression (PSD). The goal of this systematic review and meta-analysis was to critically evaluate the literature regarding the use of the neutrophil to lymphocyte ratio (NLR) as a reliable means to detect early PSD development, to help clinicians institute early interventions and improve outcomes. Methods: Electronic databases, including Web of Science, PubMed, Google Scholar, and Scopus, were searched, and eight studies were included. We assessed the certainty of the associations with GRADE methods. Results: We found that patients with PSD had higher NLR than the stroke patients with no depression (SMD = 0.51; CI 95% = 0.29-0.73, p < 0.001). Also, we found a significantly higher PLR in the patients with PSD when compared to the stroke patients with no depression (SMD = 0.66; CI 95% = 0.19-1.13, p < 0.001). Conclusion: These findings indicated that NLR and PLR could be considered inexpensive biomarkers for the prediction of PSD.

Cerebrolysin® and Environmental Enrichment, Alone or in Combination, Ameliorate Anxiety- and Depressive-Like Behaviors in a Post-Ischemic Depression Model in Mice.

OBJECTIVES: This study examined the beneficial effects of cerebrolysin (CBL) and enriched environment (EE), alone or in combination, on the neurobehavioral and molecular changes in the post-ischemic depression (PID) model in mice. MATERIALS AND METHODS: PID was induced in male Balb/c mice (25-30 g) by combining the transient bilateral common carotid artery occlusion (bCCAO), twice for 5 min at the interval of 10 min, with spatial restraint stress (2 h/day) for 2 weeks, started 48 h following the establishment of bCCAO model. Animals in the treatment groups received CBL (2.5 ml/kg) and/or were housed in EE (2 h/day) for two weeks. Anxiety- and depressive-like behaviors and sociability were evaluated the day after the last experiment. Changes in the serum corticosterone level, the hippocampal oxidative stress status, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element-binding protein (p-CREB)/CREB ratio were also detected. RESULTS: PID model induced anxiety- and depressive-like behaviors and impaired social behavior. These behavioral changes were accompanied by increased serum corticosterone level, increased lipid peroxidation, decreased antioxidant enzyme activities, reduced BDNF levels and p-CREB/CREB ratio, and increased protein levels of NF-κB and Iba-1 in the hippocampus. However, treatment with CBL and/or EE reversed behavioral and molecular changes induced by PID. CONCLUSION: Our findings imply that the model mimics many manifestations of human PID, and CBL and EE treatments, separately or in combination, are beneficial in reducing anxiety- and- depressive-like behaviors in this model.

Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats.

Impaired mitochondrial function and abnormalities in the tryptophan (Trp)-kynurenine (Kyn) pathway are linked to age-related mood disorders. This study investigated the effect of intracerebroventricular (ICV) injection of the mitochondria isolated from young rat brain on depression-like behaviors of aged rats subjected to chronic mild stress (CMS). Aged (22 months old) male rats were randomly assigned into four groups: Aged, Aged + Mit, Aged + CMS, and Aged + CMS + Mit. Anxiety- and depression-like behaviors were assessed using elevated plus maze (EPM), open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT). Mitochondrial membrane potential (MMP), ATP levels, indoleamine 2, 3-dioxygenase (IDO) levels, and Kyn metabolites were measured in the prefrontal cortex (PFC). Golgi Cox staining was used to investigate the neuronal morphology. Mitotherapy decreased immobility time and anhedonia in the FST; increased open arm time and entries in the EPM; decreased grooming and increased rearing, center time, and the entrance in the OFT. Mitotherapy also reduced IDO and Kyn metabolites, restored MMP and ATP production, and enhanced dendritic length and spine density in the PFC. Overall, mitotherapy improved anxiety-and depression-like behaviors in aged rats and it could be considered as a new therapeutic strategy for age-related depressive disorders.