A novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers.

The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

The Role of Piromelatine on Peripheral and Hippocampal Insulin Resistance in Rat Offspring Exposed to Chronic Maternal Stress.

Prenatal stress (PNS), which alters the hypothalamic-pituitary-adrenal axis function in the offspring, predisposes to insulin resistance (IR) in later life and is associated with numerous disorders, including cognitive and memory impairments. At present, our main goal is to assess the effects of chronic piromelatine (Pir) administration, a melatonin analogue, on PNS-provoked IR in the periphery and the hippocampus in male and female offspring. Pregnant Sprague-Dawley rats were exposed to chronic stress (one short-term stressor on a daily basis and one long-term stressor on a nightly basis) from the first gestation week until birth. Vehicle or Pir 20 mg/kg were administered intraperitoneally for 21 days. Plasma glucose, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) were determined as markers of peripheral IR. For the hippocampal IR assessment, insulin receptors (IRs) and glucose transporter 4 (GLUT4) were examined. Prenatally stressed offspring of both sexes indicated enhanced plasma glucose and serum insulin concentrations, increased HOMA-IR, and decreased hippocampal GLUT4 only in male rats. The PNS-induced changes were corrected by chronic treatment with Pir. The present results suggest that the melatoninergic compound Pir exerts beneficial effects on altered glucose/insulin homeostasis in PNS-exposed offspring.

Chemical Behavior and Bioactive Properties of Spinorphin Conjugated to 5,5'-Dimethyl- and 5,5'-Diphenylhydantoin Analogs.

The discovery of new peptides and their derivatives is an outcome of ongoing efforts to identify a peptide with significant biological activity for effective usage as a possible therapeutic agent. Spinorphin peptides have been documented to exhibit numerous applications and features. In this study, biologically active peptide derivatives based on novel peptide analogues of spinorphin conjugated with 5,5'-dimethyl (Dm) and 5,5'-diphenyl (Ph) hydantoin derivatives have been successfully synthesized and characterized. Scanning electron microscopy (SEM) and spectral methods such as UV-Vis, FT-IR (Fourier Transform Infrared Spectroscopy), CD (Circular Dichroism), and fluorimetry were used to characterize the microstructure of the resulting compounds. The results revealed changes in peptide morphology as a result of the restructuring of the aminoacidic sequences and aromatic bonds, which is related to the formation of intermolecular hydrogen bonds between tyrosyl groups and the hydantoin moiety. Electrochemical and fluorescence approaches were used to determine some physicochemical parameters related to the biological behavior of the compounds. The biological properties of the spinorphin derivatives were evaluated in vivo for anticonvulsant activity against the psychomotor seizures at different doses of the studied peptides. Both spinorphin analog peptides with Ph and Dm groups showed activity against all three phases of the seizure in the intravenous Pentylenetetrazole Seizure (ivPTZ) test. This suggests that hydantoin residues do not play a crucial role in the structure of spinorphin compounds and in determining the potency to raise the seizure threshold. On the other hand, analogs with a phenytoin residue are active against the drug-resistant epilepsy test (6-Hz test). In addition, bioactivity analyses revealed that the new peptide analogues have the potential to be used as antimicrobial and antioxidant compounds. These findings suggest promising avenues for further research that may lead to the development of alternative medicines or applications in various fields beyond epilepsy treatment.

Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

In Vitro Effects of Fentanyl on Aortic Viscoelasticity in a Rat Model of Melatonin Deficiency.

Melatonin influences arterial biomechanics, and its absence could cause remodeling of the arterial wall, leading to increased stiffness. Direct effects of fentanyl on the aortic wall have also been observed previously. This study aimed to evaluate in vitro the effects of fentanyl on aortic viscoelasticity in a rat model of melatonin deficiency and to test the hypothesis that melatonin deficiency leads to increased arterial wall stiffness. The viscoelasticity was estimated in strip preparations from pinealectomized (pin, melatonin deficiency) and sham-operated (sham, normal melatonin) adult rats using the forced oscillations method. In the untreated aortic wall pin, the viscoelasticity was not significantly altered. However, combined with 10-9 M fentanyl, the pin increased the natural frequency (f0) and modulus of elasticity (E') compared to the sham-operated. Independently, fentanyl treatment decreased f0 and E' compared separately to untreated sham and pin preparations. The effects of fentanyl were neither dose-dependent nor affected by naloxone, suggesting a non-opioid mechanism. Furthermore, an independent effect of naloxone was also detected in the normal rat aortic wall, resulting in reduced E'. Additional studies are needed that may improve the clinical decisions for pain management and anesthesia for certain patients with co-occurring chronic low levels of blood plasma melatonin and some diseases.

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic ß-amyloid (Aß42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

Synthesis, characterization, and biological study of new synthetic opioid hemorphin-4 peptides containing sterically restricted nonnatural amino acids.

Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH2 and Tyr-Yyy-Trp-Thr-NH2, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.

The role of melatonin deficiency induced by pinealectomy on motor activity and anxiety responses in young adult, middle-aged and old rats.

BACKGROUND: Aging affects anxiety levels in rats while the pineal gland, via its hormone melatonin, could modulate their inherited life "clock." The present study aimed to explore the impact of plasma melatonin deficiency on anxiety responses and the possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) axis and heat shock proteins (Hsp) 70 and 90 in the frontal cortex (FC) and the hippocampus in young adult, middle-aged and elderly rats with pinealectomy. RESULTS: Melatonin deficiency induced at different life stages did not affect the lifespan of rats. Pinealectomy abolished the circadian rhythm of motor activity, measured for 48 h in the actimeter, in young adult but not in middle-aged rats. Pinealectomy reduced the motor activity of the young adult rats during the dark phase and impaired the diurnal activity variations of old rats. The same generations (3- and 18 month-old rats with pinealectomy) had lower anxiety levels than the matched sham groups, measured in three tests: elevated-plus maze, light-dark test, and novelty-suppressed feeding test. While the activity of the HPA axis remained intact in young adult and middle-aged rats with melatonin deficiency, a high baseline corticosterone level and blunted stress-induced mechanism of its release were detected in the oldest rats. Age-associated reduced Hsp 70 and 90 levels in the FC but not in the hippocampus were detected. Pinealectomy diminished the expression of Hsp 70 in the FC of middle-aged rats compared to the matched sham rats. CONCLUSIONS: Our results suggest that while melatonin hormonal dysfunction impaired the motor activity in the actimeter and emotional behavior in young adult and elderly rats, the underlying pathogenic mechanism in these generations might be different and needs further verification.

Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT/ERK/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent Aß1-42 Infusion.

A reduction in melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding the molecular processes of melatonin-related signaling is critical for intervention in AD progression. Recently, we synthesized a series of melatonin analogues with donepezil fragments and tested them in silico and in vitro. In this study, one of the most potent compounds, 3c, was evaluated in a rat model of pinealectomy (pin) followed by icvAß1-42 infusion. Melatonin was used as the reference drug. Treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) had a beneficial effect on memory decline and the concomitant increase in hippocampal Aß1-42 and pTAU in the pin+icvAß1-42 rats. Melatonin supplementation facilitated non-amyloidogenic signaling via non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c analogue up-regulated the MT1A and MT2B receptors, pERK and pCREB. Our results strongly support the hypothesis that melatonin-related analogues may become a promising drug candidate for Alzheimer's disease therapy.

Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents.

Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the "intraplantar formalin" test compared to the "hot plate" test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.

Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5'-Diphenylhydantoin Schiff Bases and Phenytoin.

Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (SB1-SB4) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives SB1-Ph, SB2-Ph, SB3-Ph, and SB4-Ph, containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The SB2-Ph exhibited the highest potency to suppress the seizure spread with ED50 = 8.29 mg/kg, comparable to phenytoin (ED50 = 5.96 mg/kg). While SB2-Ph did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED50 by more than 2× and raised the protective index by more than 7× (phenytoin+SB2-Ph). The strongest correlation between in-vivo and docking study results was found for ligands' interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.

Comparative Analysis of Anticonvulsant Activity of Trans and Cis 5,5'-Diphenylhydantoin Schiff Bases.

Recently, the four 5,5'-diphenylhydantoin Schiff bases, possessing different aromatic species (SB1-Ph, SB2-Ph, SB3-Ph and SB4-Ph) were synthesized, characterized, and evaluated for anticonvulsant activity in combination with phenytoin. In the present study, the SB1-Ph and SB4-Ph compounds were selected, based on their anticonvulsant potency, and compared with their cis isomers, prepared after a one-hour exposure to the UV source, for their anticonvulsant potency in the maximal electroshock (MES) test and the kainate (KA)-induced status epilepticus (SE) test in mice. In the MES test, the cisSB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cisSB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cisSB1-Ph compound and the cisSB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to the matched control group pretreated with a vehicle, while phenytoin was ineffective in this test. The cisSB4-Ph but not the cisSB1-Ph demonstrated an antioxidant effect against the KA-induced SE in the hippocampus. Our results suggest that trans-cis conversion of 5,5'-diphenylhydantoin Schiff bases has potential against seizure spread in the MES test and mitigated the KA-induced SE. The antioxidant potency of cisSB4-Ph might be associated with its efficacy in mitigating the SE.

Synthesis, characterization and evaluation of anti-hyperalgesia, anticonvulsant and antioxidant activity of novel VV-hemorphin-5 analogs.

Two series of new VV-hemorphin-5 analogs with structures Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 and Adam-Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 , where Xxx is Ac5c (1-aminocyclopentane-1-carboxylic acid), Ac6c (1-aminocyclohexane-1-carboxylic acid), Ac7c (1-aminocycloheptane-1-carboxylic acid), and Adam is the low-molecular-weight lipophilic adamantyl building block, were synthesized, characterized electrochemically and evaluated for antioxidant, anti-hyperalgesia, and anticonvulsant activity. The design of the compounds followed the strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme. The partition coefficient value shows that the peptide scaffold goes from hydrophilic to lipophilic with the increasing size of the cycloalkane ring and even more with the introduction of the adamantane. The peptides C5-V and C7-V were the only analogs that provoked an immediate antinociceptive effect changing the mechanical pain threshold. The six new peptide analogs produced a significant and long-lasting carrageenan model of inflammatory pain in rats. While the adamantane hemorphin analog Ad7-V was the only compound with the potency to suppress psychomotor seizures in the 6-Hz test, the C6-V and Ad6-V exhibited protective activity against the seizure spread in the maximal electroshock seizure test in mice. The active analogs did not show neurotoxicity or sedative effects. Our results revealed a structure-related specific activity of a newly designed hemorphin analog that could be used as a template for future modification and preparation of compounds with potential analgesic and anticonvulsant activity.

Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer's Disease.

Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer's disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer's disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer's disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions.

Spontaneously hypertensive rats vs. Wistar Kyoto and Wistar rats: An assessment of anxiety, motor activity, memory performance, and seizure susceptibility.

Spontaneously hypertensive rats (SHRs) are widely accepted for modeling essential hypertension and Attention deficit hyperactivity disorder (ADHD). However, data concerning central nervous system changes associated with behavioral responses of this strain and usage of Wistar Kyoto (WKY) rats as controls are confounding. The objective of the present study was to assess the impact of anxiety and motor activity on the cognitive responses of SHRs compared to Wistar and WKY rats. In addition, the role of brain-derived neurotrophic factor (BDNF) in the hippocampus on cognitive behavior and seizure susceptibility in the three strains was evaluated. In Experiment#1, SHR demonstrated impulsive responses in the novelty suppression feeding test accompanied by impaired spatial working and associative memory in the Y maze and object recognition test compared with the Wistar rat but not WKY rats. In addition, the WKY rats exhibited diminished activity compared to Wistar rats in an actimeter. In Experiment#2, the seizure susceptibility was assessed by 3-min electroencephalographic (EEG) recording after two consecutive injections of pentylenetetrazol (PTZ) (20+40 mg/kg). The WKY rats were more vulnerable to rhythmic metrazol activity (RMA) than the Wistar rats. In contrast, Wistar rats were more prone to generalized tonic-clonic seizures (GTCS) than WKY rats and SHRs. Control SHR had lower BDNF expression in the hippocampus compared to Wistar rats. However, while the BDNF levels were elevated in the Wistar and WKY rats after PTZ injection, no change in this signaling molecule was observed in the SHR in the seizure condition. The results suggest Wistar rats as a more appropriate control of SHR than WKY rats for studying memory responses mediated by BDNF in the hippocampus. The higher vulnerability to seizures in Wistar and WKY rats compared to SHR might be linked to PTZ-induced decreased expression of BDNF in the hippocampus.

Oxidative Stress and Aging as Risk Factors for Alzheimer's Disease and Parkinson's Disease: The Role of the Antioxidant Melatonin.

Aging and neurodegenerative diseases share common hallmarks, including mitochondrial dysfunction and protein aggregation. Moreover, one of the major issues of the demographic crisis today is related to the progressive rise in costs for care and maintenance of the standard living condition of aged patients with neurodegenerative diseases. There is a divergence in the etiology of neurodegenerative diseases. Still, a disturbed endogenous pro-oxidants/antioxidants balance is considered the crucial detrimental factor that makes the brain vulnerable to aging and progressive neurodegeneration. The present review focuses on the complex relationships between oxidative stress, autophagy, and the two of the most frequent neurodegenerative diseases associated with aging, Alzheimer's disease (AD) and Parkinson's disease (PD). Most of the available data support the hypothesis that a disturbed antioxidant defense system is a prerequisite for developing pathogenesis and clinical symptoms of ADs and PD. Furthermore, the release of the endogenous hormone melatonin from the pineal gland progressively diminishes with aging, and people's susceptibility to these diseases increases with age. Elucidation of the underlying mechanisms involved in deleterious conditions predisposing to neurodegeneration in aging, including the diminished role of melatonin, is important for elaborating precise treatment strategies for the pathogenesis of AD and PD.

Sex-Dependent Effect of Chronic Piromelatine Treatment on Prenatal Stress-Induced Memory Deficits in Rats.

Prenatal stress impairs cognitive function in rats, while Piromelatine treatment corrects memory decline in male rats with chronic mild stress. In the present study, we aimed to evaluate the effect of chronic treatment with the melatonin analogue Piromelatine on the associative and spatial hippocampus-dependent memory of male and female offspring with a history of prenatal stress (PNS). We report that male and female young adult offspring with PNS treated with a vehicle had reduced memory responses in an object recognition test (ORT). However, the cognitive performance in the radial arm maze test (RAM) was worsened only in the male offspring. The 32-day treatment with Piromelatine (20 mg/kg, i.p.) of male and female offspring with PNS attenuated the impaired responses in the ORT task. Furthermore, the melatonin analogue corrected the disturbed spatial memory in the male offspring. While the ratio of phosphorylated and nonphosphorylated adenosine monophosphate response element binding protein (pCREB/CREB) was reduced in the two sexes with PNS and treated with a vehicle, the melatonin analogue elevated the ratio of these signaling molecules in the hippocampus of the male rats only. Our results suggest that Piromelatine exerts a beneficial effect on PNS-induced spatial memory impairment in a sex-dependent manner that might be mediated via the pCREB/CREB pathway.

Pre- and Post-Endurance Training Mitigates the Rat Pilocarpine-Induced Status Epilepticus and Epileptogenesis-Associated Deleterious Consequences.

Epilepsy is a brain disorder characterized by recurrent epileptic seizures and neurobiological, physiological, mood, and cognitive consequences. In the last decade, the beneficial effects of regular physical exercise have been investigated in patients with neurodegenerative diseases such as epilepsy. However, data on its beneficial effects and underlying mechanisms are still insufficient. The objective of the current study was to investigate the effects of endurance training, applied before and after pilocarpine (Pilo) administration, on status epilepticus (SE) severity, and its relation to epileptogenesis deleterious consequences during the chronic epileptic phase. Long-term aerobic training, applied four weeks before SE and eight weeks after SE, elevated the threshold to induce SE and reduced spontaneous motor seizures. The protective effect of this alternative approach on seizure susceptibility resulted in improved memory responses, and alleviated comorbid depression in epileptic rats. The exercised epileptic rats had improved markers of oxidative stress by decreasing lipid peroxidation and increasing the levels of glutathione and activity of superoxide dismutase in the rat hippocampus. Aerobic training managed to ameliorate the neuroinflammation by decreasing the levels of TNF-α and IL-1ß in the hippocampus. Our results suggest that regular physical training predisposes the subjects to crucial plastic changes, leading to increased resistance to SE and the development of epileptogenesis.

Significance of Antioxidants on Aging and Neurodegeneration.

The hallmark of aging is an organism's difficulty to maintain proper homeostasis, leading to a disrupted balance between the endogenous antioxidant system and the production of free radicals, a progressive inflammatory process, and increased susceptibility to (neurodegenerative diseases [...].