Protective effects of L-carnitine against Beta-amyloid-induced memory impairment and anxiety-like behavior in a rat model of Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia, leads to neurodegeneration and cognitive decline. We investigated the therapeutic effects of L-carnitine on cognitive performance and anxiety-like behavior in a rat model of AD induced by unilateral intracerebroventricular injection of ß-amyloid1-42 (Aß1-42). L-carnitine (100 mg/kg/day) was administered intraperitoneally for 28 consecutive days. Following this, the open-field test, novel object recognition test, elevated plus-maze test, Barnes maze test, and passive avoidance learning test were used to assess locomotor activity, recognition memory, anxiety-like behavior, spatial memory, and passive avoidance memory, respectively. Plasma and hippocampal oxidative stress markers, including total oxidant status (TOS) and total antioxidant capacity (TAC), were examined. In addition, histological investigations were performed in the dentate gyrus of the hippocampus using Congo red staining and hematoxylin and eosin staining. The injection of Aß1-42 resulted in cognitive deficits and increased anxiety-like behavior. These changes were associated with an imbalance of oxidants and antioxidants in plasma and the hippocampus. Also, neuronal death and Aß plaque accumulation were increased in the hippocampal dentate gyrus region. However, injection of L-carnitine improved recognition memory, spatial memory, and passive avoidance memory in AD rats. These findings provide evidence that L-carnitine may alleviate anxiety-like behavior and cognitive deficits induced by Aß1-42 through modulating oxidative-antioxidant status and preventing Aß plaque accumulation and neuronal death.

Selegiline Improves Cognitive Impairment in the Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurological disorder characterized by cognitive decline. This study was undertaken to evaluate the effects of selegiline (SEL) against AD-induced cognitive deficits and explore the possible involved mechanisms. AD was induced by unilateral intracerebroventricular (U-ICV) injection of 5 µg of amyloid beta1-42 (Aß1-42), and oral administration of SEL (0.5 mg/kg/day) was performed for 30 consecutive days. Aß injection resulted in spatial cognitive decline, as demonstrated by a decrease in the time spent in the target zone on the probe day (P < 0.01) in the Barnes maze test (BMT). This spatial cognitive decline was associated with disrupted synaptic plasticity, as indicated by reductions in both components of hippocampal long-term potentiation (LTP), namely population spike amplitude (P < 0.001) and field excitatory postsynaptic potential (P < 0.001). On the other hand, the injection of Aß resulted in oxidative stress by decreasing total thiol group (TTG) content and increasing malondialdehyde (MDA) levels in the rat plasma (P < 0.001). Additionally, the number of healthy cells in the hippocampal dentate gyrus (DG) and CA1 regions was reduced in AD rats (P < 0.001). However, oral administration of SEL improved spatial cognitive decline in the Aß-induced AD rats. The results suggest that improvement of neuroplasticity deficiency, regulation of oxidant/antioxidant status, and suppression of neuronal loss by SEL may be the mechanisms underlying its beneficial effect against AD-related spatial cognitive impairment.

The protective effect of biotin supplementation and swimming training on cognitive impairment and mental symptoms in a rat model of Alzheimer's disease: A behavioral, biochemical, and histological study.

Vitamin B (Vit B) plays a regulatory role in cognitive memory and learning. We examined the biochemical and behavioral effects of biotin supplementation (BS) and swimming training (ST) on Alzheimer's disease (AD), the most common type of dementia, in male rats. Sixty rats were randomly assigned to six groups: control, sham (receiving phosphate-buffered saline), AD (receiving a single injection of Aß into the lateral ventricle), ST (for 28 days and before Aß injection), and BS (receiving BS through oral gavage for 28 days before Aß injection). The treatments were continued until the end of the behavioral tests. Learning and memory functions were investigated through the Morris water maze (MWM) and depression and anxiety-like behaviors were tested by elevated plus-maze (EPM) and forced swimming tests. In addition, oxidative stress biomarkers, such as total thiol groups (TTG) and malondialdehyde (MDA) in serum were assessed and histological studies were performed using brain tissues. In the AD group, Aß increased the distance traveled and escape latency in the MWM, but co-administration of BS and ST attenuated the results of the MWM, EPM, and FST tests. Furthermore, BS decreased the litigious biochemical effects of Aß by enhancing the levels of TTG, in addition to reducing serum MDA levels. The use of BS as a potent antioxidant improved Aß-induced memory impairment. It attenuated oxidative stress biomarkers in the brain (number of Aß plaques) and serum of AD rats. We provide evidence for the use of BS in neurodegenerative disorders, such as AD, to elucidate the possible mechanisms.

Effect of Young Plasma Therapy on Cognition, Oxidative Stress, miRNA-134, BDNF, CREB, and SIRT-1 Expressions and Neuronal Survey in the Hippocampus of Aged Ovariectomized Rats with Alzheimer's.

Menopause may increase the risk of Alzheimer's disease (AD) dementia. This study aimed to use young plasma therapy (YPT) to improve dementia caused by AD in aged ovariectomized rats. Female Wistar rats were used in the following groups: (a) young (CY) (180-200 g, 2-3 months, n = 10) and (b) old groups (250-350 g, 22-24 months, n = 60). The old rats were randomly assigned to six sub-groups: (1) control, (2) sham, (3) ovariectomized group (OVX), (4) OVX + Alzheimer disease (OVX + AD), (5) OVX + AD+ 17ß-Estradiol (OVX + AD + E), and (6) OVX + AD + young plasma (OVX + AD + YP). Cognitive behaviors were evaluated using NOR, MWM, and PAL tests. MiR-134a, SIRT-1, CREB, and BDNF expressions were measured using real-time PCR and western blot, respectively. Oxidative stress in hippocampal tissue was assayed using ELISA kits. OVX and AD caused significant cognitive impairment (p < 0.001), up-regulated miR-134a (p < 0.001), down-regulated SIRT-1, CREB, and BDNF protein expression (p < 0.001), and decreased antioxidant marker levels (p < 0.001) compared to the sham group. YPT significantly restored miR-134a (p < 0.001), SIRT-1 (p < 0.001), CREB (p < 0.001), and BDNF (p < 0.001) protein expression in OVX + AD rats. YPT, as much as or more than estrogen therapy (ERT), significantly improved oxidative stress and down-regulated miR-134a expression and the up-regulation of SIRT-1, CREB, and BDNF proteins in OVX + AD rats (p < 0.001). YPT significantly improved histological alteration compared to the OVX + AD group (p < 0.001). As a non-pharmacological treatment, YPT can improve the expression of miR-134a and SIRT-1, CREB, and BDNF proteins as much as or more than estrogen therapy, ameliorating AD-induced dementia in aged OVX rats.

Protective effects of selegiline against amyloid beta-induced anxiety-like behavior and memory impairment.

BACKGROUND: Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aß1-42). METHODS: Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. RESULTS: The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. CONCLUSIONS: These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aß through modulation of oxidative-antioxidant status.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress.

Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aß). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aß plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aß plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aß-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aß plaque accumulation.

Coenzyme Q10 and exercise training reinstate middle cerebral artery occlusion-induced behavioral deficits and hippocampal long-term potentiation suppression in aging rats.

RATIONAL: Patients experience post-stroke cognitive impairment during aging. To date, no specific treatment solution has been reported for this disorder. OBJECTIVE: The purpose of this study was to evaluate the effects of exercise training and coenzyme Q10 supplementation on middle cerebral artery occlusion (MCAO) induced behavioral impairment, long-term potentiation inhibition and cerebral infarction size in aging rats. METHODS: Fifty aging male rats underwent MCAO surgery and were randomly distributed in to the following groups: 1-Sham, 2- control, 3- Coenzyme Q10, 4- Exercise training and 5- Exercise training with Q10 supplementation (Ex + Q10). Aerobic training groups were allowed to run on a treadmill for 12 weeks. Q10 (50 mg/kg) was administered intragastrically by gavage. Morris water maze, shuttle box and elevated plus maze tests were used to evaluate cognitive function. The population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) in the dentate gyrus area were recorded as a result of perforant pathway electrical stimulation. RESULTS: Our study showed that Q10 and aerobic training alone ameliorate spatial memory in the acquisition phase, but have no effect on spatial memory in the retention phase. Q10 and exercise training synergistically promoted spatial memory in the retention phase. Q10 and exercise training separately and simultaneously mitigated cerebral ischemia-induced passive avoidance memory impairment in acquisition and retention phases. The EPSP did not differ between the groups, but exercise training and Q10 ameliorate the PS amplitude in hippocampal responses to perforant path stimulation. Exercising and Q10 simultaneously reduced the cerebral infarction volume. CONCLUSION: Collectively, the findings of the present study imply that 12 weeks of aerobic training and Q10 supplementation alone can simultaneously reverse cerebral ischemia induced neurobehavioral deficits via amelioration of synaptic plasticity and a reduction in cerebral infarction volume in senescent rats.

Orexin-1 Receptor Antagonist SB-334867 Enhances Formalin-Induced Nociceptive Behaviors in Adult Male Rats.

Background: Orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. Neurons that produce orexin are scattered mediolaterally within the Dorsomedial Hypothalamus (DMH) and the lateral hypothalamus. In the current research, we assessed the impact of prolonged application of the antagonist of Orexin Receptor 1 (OXR1) on nociceptive behaviors in adult male rats. Methods: Sixteen Wistar rats received subcutaneous (s.c.) injections of the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle repetitively from Postnatal Day 1 (PND1)-PND30. On the 30th day following the final application of the OXR1 antagonist formalin-provoked pain was evaluated by injecting formalin. Results: Administration of the OXR1 antagonist in the long-term augmented the formalin-provoked nociceptive behaviors in interphase and phase II of the formalin-induced pain. Conclusion: Current results showed that the continued inhibiting OXR1 might be implicated in formalin-induced nociceptive behaviors. Therefore, the present study highlighted the effect of orexin on analgesia.

Quercetin-loaded nanoemulsions prevent Scopolamine-induced neurotoxicity in male rats.

Quercetin (QCT) is well-known as a neuroprotective agent due to its antioxidant capacities and reinstating mitochondrial functions. Scopolamine is commonly used as a model to induce Alzheimer's disease (AD-like) symptoms. The current study develops QCT-loaded nanoemulsion (QCT-NE) accompanied by evaluating its neuro-therapeutic effectiveness against SCO-induced neurotoxicity in male rats. The QCT-NE was prepared by the spontaneous emulsification technique and characterized by using particle size, zeta potential, drug loading, in vitro drug release behavior, and stability studies. In vivo studies were done on adult Wistar rats by applying the Morris water maze (MWM) test to study spatial memory and learning. The levels of lipid peroxidation and reduced glutathione were quantitatively determined to reveal the potential mechanism of SCO-induced oxidative stress. Finally, histological studies were performed using staining techniques. The QCT-NE particle size, zeta potential, polydispersity index (PDI), and DL were obtained at 172.4 ± 16.8 nm, -29 ± 0.26 mV, 0.3 ± 0.07, and 81.42 ± 9.14 %, respectively. The QCT and more effectively QCT-NE reduced the elevation of neurobehavioral abnormalities in the MWM test in SCO-exposed rats. The results of oxidative status showed that SCO significantly could increase the LPO and decrease the GSH levels in the rat's brain. However, QCT-NE treatment was more effective than free QCT to inhibit oxidative damage and was well correlated with histopathological findings. Taken together, QCT-NE, compared to QCT, was superior in ameliorating SCO-induced AD-like symptoms due to its better neuroprotective activity and can be considered a novel supplementary therapeutic agent in AD management.

Vitamin D Protects Against Cardiac Hypertrophy Through the Regulation of Mitochondrial Function in Aging Rats.

Cardiac aging is defined as mitochondrial dysfunction of the heart. Vitamin D (VitD) is an effective agent in ameliorating cardiovascular disorders. In this study, we indicated the protective effects of VitD against cardiac aging. Male Wistar rats were randomly divided into four groups: control (CONT), D-galactose (D-GAL): aged rats induced by D-GAL, D-GAL + Ethanol: aged rats treated with ethanol, and D-GAL + VitD aged rats treated with VitD. Aging was induced by D-GAL at 150 mg/kg via intraperitoneal injection for 8 weeks. Aged rats were treated with VitD (D-GAL + VitD) by gavage for 8 weeks. The serum samples were used to evaluate biochemical factors, and heart tissues were assessed to determine oxidative stress and gene expression. The D-GAL rats exhibited cardiac hypertrophy, which was associated with decreased antioxidant enzyme activity, enhanced oxidative marker, and changes in the expression of mitochondrial genes in comparison with the control rats. Co-treatment with VitD ameliorated all these changes. In conclusion, VitD could protect the heart against D-GAL-induced aging via enhancing antioxidant effects, and the expression of mitochondrial genes.

Role of hippocampal and prefrontal cortical cholinergic transmission in combination therapy valproate and cannabidiol in memory consolidation in rats: involvement of CREB- BDNF signaling pathways.

PURPOSE: Cognitive disorders are associated with valproate and drugs used to treat neuropsychological diseases. Cannabidiol (CBD) has beneficial effects on cognitive function. This study examined the effects of co-administration of CBD and valproate on memory consolidation, cholinergic transmission, and cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling pathway in the prefrontal cortex (PFC) and hippocampus (HPC). METHODS: One-trial, step-through inhibitory test was used to evaluate memory consolidation in rats. The intra-CA1 injection of physostigmine and atropine was performed to assess the role of cholinergic transmission in this co-administration. Phosphorylated CREB (p-CREB)/CREB ratio and BDNF levels in the PFC and HPC were evaluated. RESULTS: Post-training intraperitoneal (i.p.) valproate injection reduced memory consolidation; however, post-training co-administration of CBD with valproate ameliorated memory impairment induced by valproate. Post-training intra-CA1 injection of physostigmine at the ineffective doses in memory consolidation (0.5 and 1 µg/rat), plus injection of 10 mg/kg of CBD as an ineffective dose, improved memory loss induced by valproate, which was associated with BDNF and p-CREB level enhancement in the PFC and HPC. Conversely, post-training intra-CA1 injection of ineffective doses of atropine (1 and 2 µg/rat) reduced the positive effects of injection of CBD at a dose of 20 mg/kg on valproate-induced memory loss associated with BDNF and p-CREB level reduction in the PFC and HPC. CONCLUSION: The results indicated a beneficial interplay between valproate and CBD in the process of memory consolidation, which probably creates this interaction through the BDNF-CREB signaling pathways in the cholinergic transmission of the PFC and HPC regions.

Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

Neuroprotective effects of silymarin in 3-nitropropionic acid-induced neurotoxicity in male mice: improving behavioral deficits by attenuating oxidative stress and neuroinflammation.

3-Nitropropionic acid (3-NP) is strongly believed to be an irreversible inhibitor of mitochondrial complex II, leading to neural damage. This study aimed to investigate the neuroprotective effects of silymarin against 3-NP-induced neurotoxicity in male mice. Six-week-old mice received subacute doses of 3-NP intraperitoneally for 17 days. Mice were given silymarin (70 mg/kg/day, P.O.) for 2 weeks before 3-NP administration or for 4 weeks after 3-NP administration. At the end of the treatment schedule, animals were evaluated for behavioral alterations. Subsequently, neuronal damage in the hippocampus region of the brain tissues, oxidative stress-related parameters (lipid peroxidation, nitric oxide, superoxide dismutase, glutathione, and total antioxidant capacity), and pro-inflammatory cytokine (TNF-α, IL-17, and IL-1ß) levels were evaluated. Our results indicated that 3-NP treatment significantly (p < 0.05) tended to reduce motor coordination, memory, and neuronal antioxidant status while increasing pro-inflammatory cytokine levels. However, silymarin in both treatment and pretreatment protocols markedly (p < 0.05) attenuated the behavioral deficits, oxidative stress status, and neuroinflammation. The results of the current study suggest that the neuroprotective effect of silymarin against 3-NP-induced neurotoxicity might be due to the mitigation of oxidative stress status and provide insight into the therapeutic potential of silymarin.

The effects of carvacrol and p-cymene on Aß1-42 -induced long-term potentiation deficit in male rats.

AIMS: Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aß1-42 -induced rat model of AD. METHODS: Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aß: ICV Aß1-42 injections, Aß + CAR (50 mg/kg), Aß + p-cymene (50 mg/kg), and Aß + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aß injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. RESULTS: Aß-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aß-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. CONCLUSIONS: These data indicate that CAR or p-cymene can ameliorate Aß-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.

Effect of diminazene on cardiac hypertrophy through mitophagy in rat models with hyperthyroidism induced by levothyroxine.

Hyperthyroidism is associated with the alteration in molecular pathways involved in the regulation of mitochondrial mass and apoptosis, which contribute to the development of cardiac hypertrophy. Diminazene (DIZE) is an animal anti-infection drug that has shown promising effects on improving cardiovascular disease. The aim of the present study was to investigate the therapeutic effect of DIZE on cardiac hypertrophy and the signaling pathways involved in this process in the hyperthyroid rat model. Twenty male Wistar rats were equally divided into four groups: control, hyperthyroid, DIZE, and hyperthyroid + DIZE. After 28 days of treatment, serum thyroxine (T4) and thyroid stimulating hormone (TSH) level, cardiac hypertrophy indices, cardiac damage markers, cardiac malondialdehyde (MDA), and superoxide dismutase (SOD) level, the mRNA expression level of mitochondrial and apoptotic genes were evaluated. Hyperthyroidism significantly decreased the cardiac expression level of SIRT1/PGC1α and its downstream involved in the regulation of mitochondrial biogenesis, mitophagy, and antioxidant enzyme activities including TFAM, PINK1/MFN2, Drp1, and Nrf2, respectively, as well as stimulated mitochondrial-dependent apoptosis by reducing Bcl-2 expression and increasing Bax expression. Treatment with DIZE significantly reversed the downregulation of SIRT1, PGC1α, PINK1, MFN2, Drp1, and Nrf2 but did not significantly change the TFAM expression. Moreover, DIZE suppressed apoptosis by normalizing the cardiac expression levels of Bax and Bcl-2. DIZE is effective in attenuating hyperthyroidism-induced cardiac hypertrophy by modulating the mitophagy-related pathway, suppressing apoptosis and oxidative stress.