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

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

Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer's disease.

Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid plaques, and gradual cognitive decline. Regardless of the advances in understanding AD's pathogenesis and progression, its causes are still contested, and there are currently no efficient therapies for the illness. The post-mortem analyses revealed widespread neuronal loss in multiple brain regions in AD, evidenced by a decrease in neuronal density and correlated with the disease's progression and cognitive deterioration. AD's neurodegeneration is complicated, and different types of neuronal cell death, alone or in combination, play crucial roles in this process. Recently, the involvement of non-apoptotic programmed cell death in the neurodegenerative mechanisms of AD has received a lot of attention. Aberrant activation of necroptosis and ferroptosis, two newly discovered forms of regulated non-apoptotic cell death, is thought to contribute to neuronal cell death in AD. In this review, we first address the main features of necroptosis and ferroptosis, cellular signaling cascades, and the mechanisms involved in AD pathology. Then, we discuss the latest therapies targeting necroptosis and ferroptosis in AD animal/cell models and human research to provide vital information for AD treatment.

Neuroprotective effect of thyroid hormones on methamphetamine-induced neurotoxicity via cell surface receptors.

Thyroid hormones (THs) have an essential role in normal brain development and function. Methamphetamine (MA) is a widely abused psychostimulant that induces irreversible damages to neuronal cells. In the current study, we used rat primary hippocampal neurons (PHNs) to investigate the neuroprotective effect of THs against MA neurotoxicity. PHNs were prepared from 18-day rat embryos and cell viability was assessed using MTT assay, following treatment with various concentrations of MA, T3, T4 or tetrac, an integrin αvß3 cell surface receptor antagonist. Our results showed that 7 mM MA induced an approximately 50 % reduction in the PHNs viability. Treatment with 800 nM T3 or 8 µM T4 protected PHNs against MA toxicity, an effect which was blocked in the presence of tetrac. These findings suggest that THs protect PHNs against MA-induced cell death by the activation of integrin αvß3 cell surface receptors. So, targeting integrin αvß3 receptors or using THs can be considered as promising therapeutic strategies to overcome MA neurotoxicity.

A Review on the Disruption of Novel Object Recognition Induced by Methamphetamine.

Background: Methamphetamine (MA), is a widely abused synthetic psychostimulant that leads to irreversible brain damage manifested as cognitive impairments in humans and animals. The novel object recognition (NOR) task is a commonly used behavioral assay for the investigation of non-spatial memory in rodents. This test is based on the natural tendency of rodents to spend more time exploring a novel object than a familiar one. NOR test has been used in many studies investigating cognitive deficits caused by MA in rodents. The objective of the present study was to review neurobiological mechanisms that might be responsible for MA-induced NOR alterations. Methods: A PubMed search showed 83 publications using novel object recognition and methamphetamine as keywords in the past 10 years. Findings: The present study revealed different MA regimens cause recognition memory impairment in rodents. In addition, it was found that the main neurobiological mechanism involved in MA-induced recognition deficits is the dysfunction of monoaminergic systems. Conclusion: NOR is a useful test to assess the cognitive functions following MA administration and evaluate the efficacy of new therapeutic agents in MA-addicted individuals.

Implication of thyroid hormone receptors in methamphetamine neurocognitive effects.

Methamphetamine (MA) induces neurocognitive effects via several mechanisms. In the present study, we investigated the alteration of thyroid hormone receptor's expression in the context of MA-induced memory impairment and explored the protective effects of exogenous thyroid hormones (THs). Male wistar rats, received increasing regimen of MA (1-10 mg/kg, intraperitoneal, twice a day for 10 days), were treated with T3 (40 µg/rat/day; intranasal, 2.5 µl/nostril) or T4 (20 µg/kg/day; intraperitoneal) for 7 days after MA cessation. All rats were subjected to novel object recognition memory test and then the mRNA levels of TH nuclear receptors (TRα1 and TRß1) and seladin-1, an anti-apoptotic factor, and the protein level of TH cell surface receptor (integrin αvß3) were measured in the hippocampus of rats. Our results showed that MA-induced memory impairment is concomitant with decreased level of TRα1 mRNA. T3 or T4 treatment significantly alleviated MA-induced memory impairment, but had no significant effect on the mRNA levels of TH nuclear receptors. However, T4 treatment significantly increased the protein level of cell surface receptor (αv subunit) in MA-treated rats. These findings suggest that MA neurocognitive effects can be associated with impaired TH signaling in the brain and introduce this pathway as a promising therapeutic approach against MA-induced memory impairment.

Thyroid hormone treatment alleviates the impairments of neurogenesis, mitochondrial biogenesis and memory performance induced by methamphetamine.

Chronic use of methamphetamine (MA), a neurotoxic psychostimulant, leads to long-lasting cognitive dysfunctions in humans and animal models. Thyroid hormones (THs) have several physiological actions and are crucial for normal behavioral, intellectual and neurological development. Considering the importance of THs in the cognitive processes, the present study was designed to evaluate the therapeutic effects of THs on cognitive and neurological impairments induced by MA. Escalating doses of MA (1-10 mg/kg, IP) were injected twice daily for 10 consecutive days in rats and cognitive functions were evaluated using behavioral tests. The expression of factors involved in neurogenesis (NES and DCX), mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), neuroinflammation (GFAP, Iba-1, and COX-2) as well as Reelin and NT-3 (synaptic plasticity and neurotrophic factor, respectively) was measured in the hippocampus of MA-treated animals. The effects of three different doses of T4 (20, 40 or 80 µg/kg; intraperitoneally) or T3 (20, 40 or 80 µg/rat; 2.5 µl/nostril; intranasal) treatment, once a day for one week after MA cessation, were assessed in MA-treated rats. After the last behavioral test, serum T4 and T3 levels were measured using radioimmunoassay. The results revealed that repeated escalating regimen of MA impaired cognitive functions concomitant with neurogenesis and synaptic plasticity impairments, mitochondrial dysfunction, and neuroinflammation. T4 or T3 treatment partially decreased the alterations induced by MA. These findings suggest that THs can be considered as potential candidates for the reduction of MA abuse related neurocognitive disturbances.

Effect of three different regimens of repeated methamphetamine on rats' cognitive performance.

Neurocognitive impairment in response to methamphetamine (MA) has been proven in a variety of experimental and clinical studies. Elucidation of the underlying mechanisms of MA-induced cognitive deficits and finding preventive/therapeutic approaches need best-suited animal models. In modeling repeated MA exposure, while some believes that escalating doses simulate drug abuse conditions, others believe this regimen confers a preconditioning protection. The present study aimed to compare the effects of three different regimens of repeated MA administration on memory and cognitive function of adult rats. Rats in two different experimental groups were treated with escalating paradigms consisted of twice-daily i.p. injections; 1-4 mg/kg over 7 days or 1-10 mg/kg over 10 days. The third group received twice-daily doses of 15 mg/kg every other day over 14 days. Spatial working memory, novel object recognition task and anxiety-like behavior were measured sequentially in all MA-treated rats and vehicle-treated controls started from day 8 after last injection. All MA regimens decreased rates of spontaneous alternation in Y-maze and increased anxiety-like response. Short-term recognition memory was unchanged across all MA-treated animals, while long-term memory was impaired in the second and third MA regimen. Though MA deleterious effect especially in recognition memory is somehow dose dependent, preconditioning effect of increasing doses may be ruled out at least in the case of parameters measured here.

Intranasal insulin treatment restores cognitive deficits and insulin signaling impairment induced by repeated methamphetamine exposure.

Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3ß) and mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA-treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3ß pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse.

Neurobehavioral assessment of rats exposed to pristine polystyrene nanoplastics upon oral exposure.

The increasing use of plastics has raised concerns about pollution of freshwater by these polymeric materials. Knowledge about their potential effects on environmental and public health is limited. Recent publications have suggested that the degradation of plastics will result in the release of nano-sized plastic particles to the environment. Therefore, it is of utmost importance to gain knowledge about whether and how nanoplastics affect living organisms. The present study aimed to analyse potential neurobehavioral effects of polystyrene nanoparticles (PS-NPs) after long-term exposure on rat. Potential effects of PS-NPs were investigated using four test dosages (1, 3, 6, and 10 mg PS-NPs/kg of body weight/day) administrated orally with adult Wistar male rats for five weeks. Neurobehavioral tests were chosen to assess a variety of behavioral domains. Particle diameters in test suspensions were determined through dynamic light scattering and showed an average hydrodynamic diameter of approximately 38.92 nm. No statistically significant behavioral effects were observed in all tests performed (p > 0.05). In the elevated plus maze, PS-NPs-exposed rats showed greater number of entries into open arms compared to controls. Also, PS-NPs had no significant influence on body weight of animals. Taking into account the subtle and transient nature of neurobehavioral consequences, however, these results underline the possibility of even pristine plastic nanoparticles to induce behavioral alteration in the rest of the food web, including for marine biota and humans. Indeed even though studied neurobehavioral effects in our study was not statistically significant, the observed subtle effects may be clinically considerable.

Intranasal insulin treatment alleviates methamphetamine induced anxiety-like behavior and neuroinflammation.

Insulin, as a peptide hormone, has recently gained attention for its pro-cognitive, anti-inflammatory and neuroprotective effects in the central nervous system (CNS). Most studies have indicated anxiogenic and neuroinflammatory effects of methamphetamine (MA) and other psychostimulants, even after periods of abstinence. The present study aimed to examine whether intranasal (IN) insulin treatment with high CNS bioavailability and minimal systemic side effects, can reverse the anxiety-like behavior and neuroinflammation induced by repeated MA administration. In male wistar rats, escalating doses of MA (1-10mg/kg, i.p.) were administrated twice a day for 10 consecutive days. IN insulin treatment (0.5IU/day, for 7days after MA discontinuation) attenuated MA-induced anxiety-like behavior in the elevated plus maze task, and significantly decreased the levels of glial cell markers (GFAP and Iba1), pro-inflammatory cytokines (TNF-α and IL-6) as well as COX2 and NF-κB players of neuroinflammation, in the hippocampus of MA-treated animals. These findings introduce insulin as a potential therapeutic approach for the treatment of MA aversive symptoms.