Brain Mitochondrial Dysfunction Research Articles

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Liraglutide alleviated alpha-pyrrolidinovalerophenone (α-PVP) induced cognitive deficits in rats by modifying brain mitochondrial impairment

The use of NPS compounds is increasing, and impairment in spatial learning and memory is a growing concern. Alpha-pyrrolidinovalerophenone (α-PVP) consumption, as a commonly used NPS, can impair spatial learning and memory via the brain mitochondrial dysfunction mechanism. Liraglutide isone of the most well-known Glucagon-Like Peptide 1 (GLP-1) agonists that is used as an anti-diabetic and anti-obesity drug. According to current research, Liraglutide likely ameliorates cognitive impairment in neurodegenerative conditions and substance use disorders. Hence, the purpose of this study is examining the effect of Liraglutide on α-PVP-induced spatial learning and memory problems due to brain mitochondrial dysfunction. Wistar rats (8 in each group) received α-PVP (20 mg/kg/d for 10 consecutive days, intraperitoneally (I.P.)). Then, Liraglutide was administered at 47 and 94 μg/kg/d, I.P., for 4 weeks following the α-PVP administration. The Morris Water Maze (MWM) task evaluated spatial learning and memory 24 h after Liraglutide treatment. Bedside, brain mitochondrial activity parameters, including reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), cytochrome c release, mitochondrial outer membrane damage and swelling, and brain ADP/ATP ratio, were studied. Our results showed that Liraglutide ameliorated α-PVP-induced spatial learning and memory impairments through alleviating brain mitochondrial dysfunction (which is indicated by increasing ROS formation, collapsed MMP, mitochondrial outer membrane damage, cytochrome c release, mitochondrial swelling, and increased brain ADP/ATP ratio). This study could be used as a starting point for future studies about the possible role of Liraglutide in ameliorating mitochondrial dysfunction leading to substance use disorder- induced cognitive impairment.

#781 Cerebral vessels and early diabetic kidney disease in type 2 diabetes mellitus patients share a common mitochondrial DNA and inflammatory profile

Abstract Background and Aims Cerebrovascular disease accounts for major motor and cognitive disabilities in patients with type 2 diabetes mellitus (DM). Among the multiple pathogenic pathways which involve both the kidney and the brain vasculature, inflammation and mitochondrial dysfunction are of major importance. The aim of the study was to evaluate the association of mitochondrial DNA (mtDNA) modifications in blood and urine and of inflammatory markers with cerebral vessels structural and functional modifications in patients with type 2 DM and early diabetic kidney disease (DKD). Method A cohort of 150 patients (52 patients with normoalbuminuria, 48 patients with microalbuminuria, and 50 patients with macroalbuminuria) and 30 age- and gender-matched healthy controls were enrolled in this case series study. All patients were assessed concerning urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule dysfunction (kidney injury molecule-1-KIM-1, N-acetyl-β-(D)-glucosaminidase-NAG), serum and urinary pro-inflammatory interleukins IL-17A, IL-18, tumor necrosis factor alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1), anti-inflammatory IL-10, and eGFR (creatinine-cystatin C). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR (ABI 7900-HT–Applied BioSystem). TaqMan assays were utilized for the assessment of cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and of beta 2 microglobulin nuclear gene (B2M). mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio. The cerebrovascular hemodynamic indices were evaluated by an ultrasound equipment with high resolution (MYLAB 8-ESAOTE Italy) equipped with a Colour Ultrasound System. Subclinical atherosclerosis and arteriosclerosis were assessed by intima-media thickness (IMT) in the common carotid arteries (CCAs), Gosling's pulsatility index (PI) and Pourcellot's resistivity index (RI) in the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), bilaterally. Cerebrovascular reactivity (CVR), which represents the vasodilatory reactivity of cerebral vessels in response to a vasodilatory stimulus, was assessed by the breath-holding test where hypercapnia was the vasodilatory stimulus and the breath-holding index (BHI) was calculated. Results Multivariable linear analysis revealed direct correlations of serum TNFα with UACR, KIM-1, NAG, and urinary mtDNA, and a negative correlation with serum mtDNA (R2 = 0.893; p < 0.0001); urinary TNFα correlated directly with UACR, KIM-1, NAG, and urinary mtDNA (R2 = 0.693; p < 0.0001). Serum ICAM-1 had a direct correlation with UACR, KIM-1, NAG, synaptopodin, and podocalyxin, and a negative one with serum mtDNA (R2 = 0.855; p < 0.0001). Urinary ICAM-1 correlated directly with UACR, KIM-1, NAG, and urinary mtDNA, and indirectly with eGFR (R2 = 0.783; p < 0.0001). CCA-IMT had a direct correlation with serum IL-17A and indirect correlations with serum mtDNA and serum IL-10 (R2 = 0.706; p < 0.0001); ICA-PIs and MCA-PIs correlated directly with serum IL-17A and negatively with serum IL-10, respectively (R2 = 0.567; R2 = 0.642; p < 0.0001). ICA-RIs showed a direct correlation with UACR, serum and urinary IL-17A, serum and urinary IL-18, NAG, and urinary TNFα, and a negative correlation with serum mtDNA and with serum and urinary IL-10 (R2 = 0.930; p < 0.0001). MCA-RIs correlated directly with UACR, serum IL-17A, serum IL-18, NAG, urinary mtDNA, and urinary TNFα, and negatively with serum mtDNA and serum IL-10 (R2 = 0.875; p < 0.0001). BHI correlated directly with serum IL-10 and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG (R2 = 0.823; p < 0.0001). Conclusion In neurologically asymptomatic type 2 DM patients there is an association of mtDNA changes in blood and urine with cerebral vessels atherosclerotic and arteriosclerotic remodeling, as well as with decreased CVR. MtDNA modifications may exert their effect in parallel with markers of inflammation at both kidney and cerebrovascular level from the early stages of DKD.

Hyperoxia and brain: the link between necessity and injury from a molecular perspective.

Oxygen (O2) supplementation is commonly used to treat hypoxia in patients with respiratory failure. However, indiscriminate use can lead to hyperoxia, a condition detrimental to living tissues, particularly the brain. The brain is sensitive to reactive oxygen species (ROS) and inflammation caused by high concentrations of O2, which can result in brain damage and mitochondrial dysfunction, common features of neurodegenerative disorders. Hyperoxia leads to increased production of ROS, causing oxidative stress, an imbalance between oxidants and antioxidants, which can damage tissues. The brain is particularly vulnerable to oxidative stress due to its lipid composition, high O2 consumption rate, and low levels of antioxidant enzymes. Moreover, hyperoxia can cause vasoconstriction and decreased O2 supply to the brain, posing a challenge to redox balance and neurodegenerative processes. Studies have shown that the severity of hyperoxia-induced brain damage varies with inspired O2 concentration and duration of exposure. Therefore, careful evaluation of the balance between benefits and risks of O2 supplementation, especially in clinical settings, is crucial.

Oxidative stress and mitochondrial dysfunction in brain of vinclozolin exposed animals

Vinclozolin (VCZ) is a widely used fungicide in agriculture, especially in fruits and wine. Various studies have detailed the effects of VCZ exposure on different organs, but no information is available on its effects on brain tissues. This paper investigated the effects of VCZ exposure on the oxidative stress and mitochondrial dysfunction in brain tissue. C57BL/6 mice were exposed to VCZ (100 mg/kg) by oral gavage for 28 days. Mitochondrial homeostasis, often known as mitochondrial quality control, involves a range of processes, including mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy and autophagy. VCZ administration modified the mRNA expression levels of Sirt1, Sirt3, PGC-1α, TFAM, Nrf1, VDAC-1 and Cyt c in brain tissue, as compared to control animals (CTR). The analyses also showed increased oxidative stress, in particular VCZ administration reduced SOD and CAT activities and GSH levels while increased T-AOC levels and lipid peroxidation. Additionally, brain tissues from VCZ group showed DNA oxidation (increased PARP-1 immunostaining) and apoptosis (increased TUNEL+ cells, increased expression of Bax mRNA level and reduced Bcl-2 levels). Western blot and immunohistochemical analyses showed increased mitophagic pathway with the accumulation of PINK1 and Parkin in mitochondria. Additionally, autophagic pathway was also increased with the increased expression and colocalization of LC3 with Neun and GFAP. Overall, this study showed that chronic VCZ exposure impaired mitochondrial homeostasis and increased oxidative stress in brain tissues.

Mitochondrial Fusion Promoter Given During Ischemia Has Greater Neuroprotective Efficacy Than When Given at Onset of Reperfusion in Rats with Cardiac Ischemia/Reperfusion Injury.

Cardiac ischemia/reperfusion (I/R) injury has been shown to impose deleterious effects not only on the heart but also on the brain. Our previous study demonstrated that pretreatment with a mitochondrial fusion promoter (M1) provided central neuroprotective effects following cardiac I/R injury. To investigate the effects of M1 given during the ischemic phase and M1 given at the beginning of reperfusion on brain pathologies following cardiac I/R. Male Wistar rats were randomly divided into either a sham operation (n = 6) or cardiac I/R injury (n = 18) group. Rats with cardiac I/R injury were then randomly divided into 3 subgroups: 1) Control, 2) M1 treatment during cardiac ischemia (2 mg/kg, intravenous (i.v.)), and 3) M1 treatment at the beginning of reperfusion (2 mg/kg, i.v.). After euthanasia, the brain of each rat was removed for further analysis. Cardiac I/R injury caused brain mitochondrial dynamic imbalance, brain mitochondrial dysfunction, brain apoptosis, microglial dysmorphology, brain inflammation, tau hyperphosphorylation, and synaptic dysplasticity. M1 treatment at both time points effectively improved these parameters. M1 given during the ischemic phase had greater efficacy with regard to preventing brain mitochondrial dysfunction and suppressing brain inflammation, when compared to M1 given at the beginning of reperfusion. Our findings suggest that treatment with this mitochondrial fusion promoter prevents mitochondrial dynamic imbalance in the brain of rats with cardiac I/R injury, thereby attenuating brain pathologies. Interestingly, giving the mitochondrial fusion promoter during the ischemic phase exerted greater neuroprotection than if given at the beginning of reperfusion.

Western diet-induced obesity results in brain mitochondrial dysfunction in female Ossabaw swine.

Diet-induced obesity is implicated in the development of a variety of neurodegenerative disorders. Concurrently, the loss of mitochondrial Complex I protein or function is emerging as a key phenotype across an array of neurodegenerative disorders. Therefore, the objective of this study was to determine if Western diet (WD) feeding in swine [carbohydrate = 40.8% kCal (17.8% of total calories from high fructose corn syrup), protein = 16.2% kcal, fat = 42.9% kCal, and 2% cholesterol] would result in Complex I syndrome pathology. To characterize the effects of WD-induced obesity on brain mitochondria in swine, high resolution respirometry measurements from isolated brain mitochondria, oxidative phosphorylation Complex expression, and indices of oxidative stress and mitochondrial biogenesis were assessed in female Ossabaw swine fed a WD for 6-months. In line with Complex I syndrome, WD feeding severely reduced State 3 Complex I, State 3 Complex I and II, and uncoupled mitochondrial respiration in the hippocampus and prefrontal cortex (PFC). State 3 Complex I mitochondrial respiration in the PFC inversely correlated with serum total cholesterol. WD feeding also significantly reduced protein expression of oxidative phosphorylation Complexes I-V in the PFC. WD feeding significantly increased markers of antioxidant defense and mitochondrial biogenesis in the hippocampi and PFC. These data suggest WD-induced obesity may contribute to Complex I syndrome pathology by increasing oxidative stress, decreasing oxidative phosphorylation Complex protein expression, and reducing brain mitochondrial respiration. Furthermore, these findings provide mechanistic insight into the clinical link between obesity and mitochondrial Complex I related neurodegenerative disorders.

Administration of mitochondrial fusion promoter during ischemia and at the onset of reperfusion exert neuroprotective effects in rats with cardiac ischemia/reperfusion injury

AbstractBackgroundAcute myocardial infarction (AMI) is one of the fetal cardiovascular diseases and a leading cause of death (1, 2). Our previous study demonstrated that pretreatment of mitochondrial fusion promoter (M1) provided neuroprotective effects on the brain following cardiac ischemia/reperfusion (I/R) injury (3). However, the effects of M1 given during ischemia and M1 given at the onset of reperfusion on brain pathologies following cardiac I/R have never been investigated.MethodSixteen male Wistar rats were randomly divided into either a sham‐operation (n = 8) or cardiac I/R (n = 24). In the cardiac I/R group, rats were then randomly divided into 3 subgroups, including the I/R operation with vehicle (0.9% sodium chloride solution for 15 minutes before I/R protocol, intravenous (i.v.) injection), the I/R operation with M1 administration during cardiac ischemia (2 mg/kg, 15 minutes after left anterior descending (LAD) coronary artery ligation, i.v. injection), and the I/R operation with M1 administration at the onset of reperfusion group (2 mg/kg at the beginning of reperfusion, i.v. injection). At the end of experimental protocol, rats were sacrificed and brains were obtained for further molecular investigation.ResultThe results demonstrated that cardiac I/R increased brain inflammation, caused microglial dysmorphology, caused brain mitochondrial dysfunction, increased tau hyperphosphorylation, and increased brain apoptosis (p<0.05, Figure 1). M1 given during ischemia and M1 given at the onset of reperfusion effectively attenuated brain pathologies following cardiac I/R by preserving microglial morphology, improving brain mitochondrial function, decreasing tau hyperphosphorylation, and decreasing brain apoptosis (p<0.05, Figure 1). Interestingly, M1 given during ischemia had better efficacy to suppressing brain inflammation, when compared to M1 given at the onset of reperfusion apoptosis (p<0.05, Figure 1).ConclusionThese findings suggest the administration of mitochondrial fusion promoter effectively decreased brain pathologies following cardiac I/R. The administration of mitochondrial fusion promoter during ischemia had greater suppression on brain inflammation than administration at the onset of reperfusion. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for cardiac I/R injury.

Pharmacologically targeted mitochondrial fission/fusion performs neuroprotection against trastuzumab‐induced cognitive deficits in rats via suppressing mitochondrial dysfunction and oxidative stress

AbstractBackgroundTrastuzumab (TRZ) has been utilized primarily as a chemotherapeutic treatment for advanced human epidermal growth factor receptor type 2‐expressing malignant tumors. Regardless, TRZ‐associated neurotoxicity has emerged as an adverse clinical complication of oncologic therapy by increasing oxidative stress and damaging mitochondrial function. As the neuroprotective effects of mitochondrial fission inhibitor (MDV) and fusion promoter (M1) have been illustrated for a variety of neurological pathologies, the anti‐neurotoxic mechanisms of MDV and M1 against TRZ are unknown.MethodTwenty male Wistar rats were randomly divided into either the TRZ group (4 mg/kg/day for 7 days, I.P., n = 15) or the control group (CON, n = 5). In the TRZ group, rats also received one of the following co‐treatments: 1) vehicle (VEH, n = 5), 2) MDV (1.2 mg/kg/day, n = 5), or 3) M1 (2 mg/kg/day, n = 5) via I.P. injection for 7 days. Subsequently, novel object location (NOL) and novel object recognition (NOR) tests for long‐term learning and memory were performed. Then, the brain tissue was used for determining mitochondrial functions, and the blood serum was also used to measure the oxidative stress levels.ResultTRZ (the VEH group) increased brain mitochondrial dysfunction and systemic oxidative stress via increasing reactive oxygen species (ROS) production, mitochondrial depolarization, mitochondrial swelling, and serum malondialdehyde levels, respectively, when compared to the CON group (p<0.05, Figure 1). TRZ (the VEH group) impaired long‐term learning and memory, as indicated by the attenuated percentage preference index of NOL and NOR tests, compared to the CON group (p<0.05, Figure 1). MDV and M1 co‐therapies exerted neuroprotection by rescuing brain mitochondrial function and systemic oxidative stress, resulting in the restoration of long‐term cognitive parameters (p<0.05, Figure 1).ConclusionTargeting brain mitochondrial dynamics could be an effective remedy against TRZ‐induced cognitive impairment in rats via suppressing mitochondrial dysfunction and oxidative stress. Therefore, pharmacological inhibition of mitochondrial fission and promotion of mitochondrial fusion could be a novel anti‐neurotoxicity‐induced by TRZ.

Protective role of hesperetin in sorafenib-induced hepato- and neurotoxicity in mice via modulating apoptotic pathways and mitochondrial reprogramming

IntroductionSorafenib, an FDA-approved standard chemotherapy for advanced hepatocellular carcinoma, is associated with numerous adverse effects that significantly impact patients' physiological well-being. Consequently, identifying agents that mitigate these side effects while enhancing efficacy is crucial. Hesperetin, a flavone present in fruits and vegetables, possesses antioxidant, anti-inflammatory, and anti-cancer properties. This study aimed to investigate the hepatotoxic and neurotoxic effects of sorafenib and the potential protective role of hesperetin. Materials and methodsSwiss albino mice were orally administered sorafenib (100 mg/kg) alone or in combination with hesperetin (50 mg/kg) over 21 days. Behavioral assessments for anxiety and depressive-like behaviors were conducted. Additionally, evaluations encompassed apoptotic activity, mitochondrial integrity, liver enzyme levels, proliferation rates, and histopathological changes. ResultsCombining hesperetin with sorafenib showed improvements in behavioral alterations, liver damage, brain mitochondrial dysfunction, and liver apoptosis compared to the sorafenib-only group in mice. ConclusionHesperetin exhibits potential as an adjunct to sorafenib, mitigating its side effects by attenuating its toxicity, enhancing efficacy, and potentially reducing the occurrence of sorafenib-induced resistance through the downregulation of hepatocyte growth factor levels.

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Iron Responsiveness to Lysosomal Disruption: A Novel Pathway to Alzheimer's Disease.

Familial Alzheimer's disease (fAD) mutations in the amyloid-β protein precursor (AβPP) enhance brain AβPP C-Terminal Fragment (CTF) levels to inhibit lysosomal v-ATPase. Consequent disrupted acidification of the endolysosomal pathway may trigger brain iron deficiencies and mitochondrial dysfunction. The iron responsive element (IRE) in the 5'Untranslated-region of AβPP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent AβPP translation and levels APP-CTFβ in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of AβPP is part of the neuroprotective function of sAβPPα with its role in iron transport.

Research progress of postoperative cognitive dysfunction in cardiac surgery under cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is often used in cardiothoracic surgery because its nonphysiological state causes pathophysiological changes in the body, causing multiorgan and multitissue damage to varying degrees. Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after cardiac surgery. The etiology and mechanism of POCD are not clear. Neuroinflammation, brain mitochondrial dysfunction, cerebral embolism, ischemia, hypoxia, and other factors are related to the pathogenesis of POCD. There is a close relationship between CPB and POCD, as CPB can cause inflammation, hypoxia and reperfusion injury, and microemboli formation, all of which can trigger POCD. POCD increases medical costs, seriously affects patients' quality of life, and increases mortality. Currently, there is a lack of effective treatment methods for POCD. Commonly used methods include preoperative health management, reducing inflammation response during surgery, preventing microemboli formation, and implementing individualized rehabilitation programs after surgery. Strengthening preventive measures can minimize the occurrence of POCD and its adverse effects.

Treatment with apoptosis inhibitor restores cognitive impairment in rats with myocardial infarction

We previously reported that apoptosis is responsible for cognitive impairment in rats with myocardial infarction (MI). Acute administration of an apoptosis inhibitor (Z-vad) effectively reduced brain inflammation in rats with cardiac ischemia/reperfusion injury. However, the beneficial effects of Z-vad on cognitive function, brain inflammation, mitochondrial function, cell death pathways, and neurogenesis in MI rats have not been investigated. Male rats were divided into sham or MI groups (left anterior descending coronary ligation). A successful MI was determined by a reduction of ejection fraction <50 %. Then, MI rats were allocated to receive vehicle, enalapril (10 mg/kg, a positive control), and Z-vad (1 mg/kg) for 4 weeks. Cardiac function, cognitive function, and molecular analysis were investigated. MI rats exhibited cardiac dysfunction, cognitive impairment, blood brain barrier (BBB) breakdown, dendritic spine loss, which were accompanied by an upregulation of oxidative stress, mitochondrial dysfunction, and apoptosis. Chronic treatment with Z-vad attenuated cardiac dysfunction following MI to the same extent as enalapril. Z-vad successfully improved cognitive function and restored dendritic spine density in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction similar to enalapril. Moreover, Z-vad provided greater efficacy than enalapril in enhancing mitophagy, neurogenesis, synaptic proteins and reducing apoptosis in hippocampus of MI rats. Nevertheless, neither Z-vad nor enalapril increased BBB tight junction protein. In conclusion, treatment with an apoptosis inhibitor reduced cognitive impairment in MI rats via reducing oxidative stress, mitochondrial dysfunction, apoptosis, and restoring dendritic spine density, together with enhancing mitophagy and neurogenesis.

Potential role of creatine as an anticonvulsant agent: evidence from preclinical studies.

Epilepsy is one of the most common neurological disorders affecting people of all ages representing a significant social and public health burden. Current therapeutic options for epilepsy are not effective in a significant proportion of patients suggesting a need for identifying novel targets for the development of more effective therapeutics. There is growing evidence from animal and human studies suggesting a role of impaired brain energy metabolism and mitochondrial dysfunction in the development of epilepsy. Candidate compounds with the potential to target brain energetics have promising future in the management of epilepsy and other related neurological disorders. Creatine is a naturally occurring organic compound that serves as an energy buffer and energy shuttle in tissues, such as brain and skeletal muscle, that exhibit dynamic energy requirements. In this review, applications of creatine supplements in neurological conditions in which mitochondrial dysfunction is a central component in its pathology will be discussed. Currently, limited evidence mainly from preclinical animal studies suggest anticonvulsant properties of creatine; however, the exact mechanism remain to be elucidated. Future work should involve larger clinical trials of creatine used as an add-on therapy, followed by large clinical trials of creatine as monotherapy.

Metformin Exerted Neuroprotective Effects on Cognition in Rats with Trastuzumap‐Induced Brain Toxicity

AbstractBackgroundTrastuzumap (Trz) is effectively used for breast cancer patients to improve health status and reduce mortality rate. Nevertheless, several studies reported its adverse effect on brain toxicity. To date, the mechanisms of Trz‐induced brain toxicity are not fully understood. Metformin is a generic prescribed drug for type 2 diabetes mellitus, while in the past decade it also used for attenuating the adverse effects of chemotherapy. However, the effects of metformin on brain mitochondrial function, hippocampal microglial function, hippocampal synaptic plasticity, and cognitive function in Trz‐induced brain toxicity have never been investigated.MethodEighteen male Wistar rats were randomly divided into two groups; control group (0.9% NSS, intraperitoneal (i.p.) injection, n = 8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n = 16). Then, Trz‐treated rats were divided into two subgroups (n = 6/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or metformin (250 mg/kg/day for 7 days, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation.ResultTrz‐treated rats demonstrated an increase of mitochondrial ROS production, increased mean fluorescence intensity of ionized calcium binding adaptor molecule 1 (Iba1), decreased hippocampal dendritic spine density, decreased preferent index in novel object location (NOL) and novel object recognition (NOR) test (p&lt;0.05, Figure 1A‐F). Metformin‐treated in Trz‐rats reversed the adverse effect of Trz by attenuated mitochondrial ROS production, decreased mean fluorescence intensity of Iba1, increased hippocampal dendritic spine density, as well as increased preferent index in NOL and NOR test (p&lt;0.05, Figure 1A‐F).ConclusionTrz‐induced brain toxicity as indicated by brain mitochondrial dysfunction, decreased hippocampal microglial function, impaired hippocampal synaptic plasticity, and cognitive dysfunction, while metformin alleviated those deleterious effects. The findings in this study emphasize the roles of metformin against Trz‐induced brain toxicity and strengthen

Mitochondrial dynamic modulators improve cognitive function in rats with myocardial infarction

AbstractBackgroundCognitive impairment is the most frequent mental health problem among people with heart failure (HF). Brain pathologies in HF‐induced cognitive impairment are possibly associated with the imbalance of brain mitochondrial dynamics. Therefore, therapeutic interventions targeting mitochondrial dynamics by mitochondrial fission inhibition or mitochondrial fusion enhancement would provide beneficial outcomes to the brain of HF subjects. This study aimed to test whether modulating mitochondrial dynamic improves cognitive function in HF rats via reduced brain mitochondrial dysfunction, and dendritic spine loss.MethodRats underwent either sham surgery or permanent left anterior descending coronary artery ligation‐induced myocardial infarction (MI). MI rats developed HF with reduced ejection fraction (%LVEF &lt;50%) at 1‐week post‐operation. Then, MI rats were assigned to receive one of four following interventions: (1) DMSO as a vehicle, (2) enalapril (a positive control, 10 mg/kg/day, orally), (3) mitochondrial division Inhibitor (Mdivi‐1, 1.2 mg/kg/day, intraperitoneal (IP) injection), (4) mitochondrial fusion promotor (M1, 2 mg/kg/day, IP injection). All rats were received the intervention for 4 weeks, then, the cognitive function via NOL was assessed, and were sacrificed. Brain mitochondrial function and dendritic spine density were determined.ResultHF rats developed cognitive impairment, when compared to the sham group, and it was associated with increased brain mitochondrial oxidative stress, and dendritic spine loss in hippocampus (Figure). Treatment with Mdivi‐1 and M1 improved cognitive function similar to enalapril, as indicated by increasing %preference of NOL. Furthermore, all treatments effectively reduced brain mitochondrial ROS levels and hippocampal dendritic spine loss in HF rats (Figure).ConclusionMitochondrial fusion inhibitor and mitochondrial fusion improved cognitive function in HF rats through a reduction of mitochondrial ROS levels and preserved dendritic spine density.

GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation and Neurotrophic Factors to Reverse Age-Associated Cognitive Decline: Implications for Improving Brain Health in Aging.

Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we studied young (20-week) and old (90-week) C57BL/6J mice. Old mice received either regular or GlyNAC supplemented diets for 8 weeks, while young mice received the regular diet. Cognition and brain outcomes (GSH, OxS, mitochondrial energetics, autophagy/mitophagy, glucose transporters, inflammation, genomic damage and neurotrophic factors) were measured. Compared to young mice, the old-control mice had significant cognitive impairment and multiple brain defects. GlyNAC supplementation improved/corrected the brain defects and reversed ACD. This study finds that naturally-occurring ACD is associated with multiple abnormalities in the brain, and provides proof-of-concept that GlyNAC supplementation corrects these defects and improves cognitive function in aging.

High fat diet feeding induces brain mitochondrial dysfunction in female Ossabaw swine

Study objective: Emerging evidence now suggest reduced mitochondrial function as a key initiator in Alzheimer’s disease (AD)-like pathology increasing the need for models of AD that display mitochondrial dysfunction. Dyslipidemia is a common aliment from overconsumption of a high fat diet (HFD) that increases the risk of AD and may contribute to mitochondrial dysfunction. Rodent studies utilize HFDs to induce brain pathology resembling that of AD. Unsurprisingly, rodent studies are rarely recapitulated in humans, which leads to a very low clinical success rate and highlights the need for more translatable models to study AD-like pathology. Swine seem to share many characteristics of humans and might offer a more translatable model to study HFD induced pathology. Thus, the objective of this study was to determine if HFD feeding in swine could offer a more translatable model to study mitochondrial dysfunction during neurodegeneration. Hypothesis: 6-months of HFD feeding will decrease indices of mitochondrial function and biogenesis in female Ossabaw swine. Methods: To characterize the effects of a HFD on brain mitochondrial health in a highly translatable swine model, high resolution respirometry measurements were taken from isolated brain mitochondria from in female Ossabaw swine fed a HFD for 6-months. Additionally, indices of mitochondrial biogenesis in whole tissue was measured (transcriptional markers of biogenesis and citrate synthase activity). Results: HFD feeding significantly increased body weight (p&lt;0.05) with trending increases in blood glucose (p&lt;0.10). Maximal uncoupled mitochondrial respiration was significantly decreased (p&lt;0.05) with state 3-complex I and state 3 complex I &amp; II trending down in the dorsal hippocampus (DH) after HFD diet feeding (p&lt;0.10). Additionally, state 2 respiration was significantly decreased in the prefrontal cortex (PFC) after HFD feeding (p&lt;0.05). HFD feeding increased transcriptional markers of mitochondrial biogenesis in the DH and PFC (p&lt;0.05), without altering whole homogenate citrate synthase activity in either brain region. Conclusions: These data indicate HFD feeding in Ossabaw pigs could offer a potential model to study pathologies relating to mitochondrial dysfunction during neurodegenerative process. Additionally, the DH was found to be more vulnerable to HFD-induced perturbations, evident by the exacerbated deficits in mitochondrial respiration in this brain region. Finally, these data suggest HFD-induced increase in transcriptional markers of mitochondrial biogenesis may be a compensatory response to HFD-induced mitochondrial respiration deficits. However, citrate synthase activity was not different between groups indicating this upregulation of transcriptional markers was unable to translate to an increase in mitochondrial content in the DH and PFC. The project was supported by the MU Office of Postdoctoral Education Research Grant Program. Additional funding was also generously provided Scott Rector. Images in figure 2 adapted and modified from “Krebs cycle template”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates . This work was also supported with resources and the use of facilities at the University of Missouri and Harry S. Truman Memorial Veterans Hospital in Columbia, Missouri. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pre- and post-treatment of α-Tocopherol on cognitive, synaptic plasticity, and mitochondrial disorders of the hippocampus in icv-streptozotocin-induced sporadic Alzheimer's-like disease in male Wistar rat.

Most dementia cases in the elderly are caused by Alzheimer's disease (AD), a complex, progressive neurological disease. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rat's results in aberrant brain insulin signaling, oxidative stress, and mitochondrial dysfunction that impair cognition change neural plasticity, and eventually lead to neuronal death. The current study aims to define the neuroprotective action of alpha-tocopherol in enhancing mitochondrial function and the function of synapses in memory-impaired rats brought on by icv-STZ. Male Wistar rats were pre-treated with (α-Tocopherol 150 mg/kg) orally once daily for 7 days before and 14 days after being bilaterally injected with icv-STZ (3 mg/kg), while sham group rats received the same volume of STZ solvent. After 2 weeks of icv-STZ infusion, rats were tested for cognitive performance using a behaviors test and then were prepared electrophysiology recordings or sacrificed for biochemical and histopathological assays. The cognitive impairment was significantly minimized in the behavioral paradigms for those who had taken α-Tocopherol. In the hippocampus of icv-STZ rat brains, α-Tocopherol ocopherol effectively prevented the loss of glutathione levels and superoxide dismutase enzyme activity, lowered mitochondrial ROS and mitochondrial membrane potential, and also brought about a decrease in Aβ aggregation and neuronal death. Our findings demonstrated that by lowering neurobehavioral impairments caused by icv-STZ, oxidative stress, and mitochondrial dysfunction, α-Tocopherol enhanced intracellular calcium homeostasis and corrected neurodegenerative defects in the brain. These findings examine the available approach for delaying AD connected to mitochondrial malfunction and plasticity issues.