Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats.

N-nitrosodiethylamine (NDEA) is a potential carcinogen known to cause liver tumors and chronic inflammation, diabetes, cognitive problems, and signs like Alzheimer's disease (AD) in animals. This compound is classified as probably carcinogenic to humans. Usual sources of exposure include food, beer, tobacco, personal care products, water, and medications. AD is characterized by cognitive decline, amyloid-ß (Aß) deposit, tau hyperphosphorylation, and cell loss. This is accompanied by neuroinflammation, which involves release of microglial cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1ß (IL-1ß), by nuclear factor kappa B (NF-κB) upregulation; each are linked to AD progression. Weak PI3K/Akt insulin-signaling inhibits IRS-1 phosphorylation, activates GSK3ß and promotes tau hyperphosphorylation. Metformin, an antihyperglycemic agent, has potent anti-inflammatory efficacy. It reduces proinflammatory cytokines such as IL-6, IL-1ß, and TNF-α via NF-κB inhibition. Metformin also reduces reactive oxidative species (ROS) and modulates cognitive disorders reported due to brain insulin resistance links. Our study examined how NDEA affects spatial memory in Wistar rats. We found that all NDEA doses tested impaired memory. The 80 µg/kg dose of NDEA increased levels of Aß1-42, TNF-α, and IL-6 in the hippocampus, which correlated with memory loss. Nonetheless, treatment with 100 mg/kg of metformin attenuated the levels of pro-inflammatory cytokines and Aß1-42, and enhanced memory. It suggests that metformin may protect against NDEA-triggered memory issues and brain inflammation.

Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3ß decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model.

Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3ß (p-GSK3ß) and total GSK3ß levels were determined, and importantly GSK3ß regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3ß levels, while total GSK3ß did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3ß levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3ß levels in neither the hippocampus nor PFC. Total GSK3ß levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3ß levels, a kinase key of signaling cascade of insulin receptor.

Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview.

Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments (d-amphetamine and methylphenidate) are evaluated.

Serotonin transporter and memory.

The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to memory. Therefore, we made an attempt to summarize and discuss the available publications implicating the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that Alzheimer's disease and drugs of abuse like d-methamphetamine (METH) and (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") have been associated to decrements in the SERT expression and memory deficits. Several reports have indicated that memory formation and amnesia affected the SERT expression. The SERT expression seems to be a reliable neural marker related to memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular mechanisms associated to these changes are of great importance for investigation.

5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes.

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) improve memory and reverse amnesia, although the mechanisms involved are poorly understood. Hence, in this paper an attempt was made to summarize recent findings. Available evidence indicates that diverse 5-HT6 receptor antagonists produce promnesic and/or antiamnesic effects in diverse conditions, including memory formation, age-related cognitive impairments, memory deficits in diseases such as schizophrenia, Parkinson, and Alzheimer's disease (AD). Notably, some 5-HT6 receptor agonists seem to have promnesic and/or antiamnesic effects. At the present, it is unclear why 5-HT6 receptor agonists and antagonists may facilitate memory or may reverse amnesia in some memory tasks. Certainly, 5-HT6 drugs modulate memory, which are accompanied with neural changes. Likewise, memory, aging, and AD modify 5-HT6 receptors and signaling cascades. Further investigation in different memory tasks, times, and amnesia models together with more complex control groups might provide further clues. Notably, human studies suggest a potential utility of 5-HT6 receptor antagonists in mild-to-moderate AD patients. Even individuals with mild cognitive impairment (MCI) offer a great opportunity to test them.