Search

Neurodegenerative disorders represent a significant and growing health burden worldwide. Unfortunately, limited therapeutic options are currently available despite ongoing efforts. Over the past decades, research efforts have increasingly focused on understanding the molecular mechanisms underlying these devastating conditions. Orphan receptors, a class of receptors with no known endogenous ligands, emerge as promising druggable targets for diverse diseases. This review aims to direct attention to a subgroup of orphan GPCRs, in particular class A orphans that have roles in neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Multiple sclerosis. We highlight the diverse roles orphan receptors play in regulating critical cellular processes such as synaptic transmission, neuronal survival and neuro-inflammation. Moreover, we discuss the therapeutic potential of targeting orphan receptors for the treatment of neurodegenerative disorders, emphasizing recent advances in drug discovery and preclinical studies. Finally, we outline future directions and challenges in orphan receptor research. [ABSTRACT FROM AUTHOR]

Introduction: This study investigates the effects of social isolation on mental health and cognitive functions in Sprague Dawley (SD) and Wistar Albino (WIS) rat strains, prompted by the heightened awareness of such impacts amid the COVID-19 pandemic. This study aims to explore the impact of social isolation on memory, learning, and behavioral changes in middle-aged SD and WIS rat strains and to investigate cortical trace element levels, seeking potential correlations between these levels and the observed behavioral responses to social isolation. Methods: Four groups of 14-month-old male rats were established: control and isolated SDs and WIS rats (CONT-SD, ISO-SD, CONT-WIS, ISO-WIS). Morris Water Maze and Porsolt Forced Swimming tests were conducted for behavioral assessment. Following behavioral tests, rats were sacrificed under general anesthesia, and cortices were isolated for analysis of macro and trace element levels (ICP/MS). Results: In behavioral tests, CONT-SD rats exhibited superior performance in the Morris Water Maze test compared to CONT-WIS rats, but displayed increased depressive behaviors following social isolation, as evident in the Porsolt Forced Swimming test (p < 0.05). ISO-SD rats showed elevated levels of Co and Cu, along with reduced levels of Cs and As, compared to ISO-WIS rats. Moreover, isolation resulted in decreased Cu and Mo levels but increased Rb levels in WIS rats. Comparison of trace element levels in naïve groups from different strains revealed lower Zn levels in the WIS group compared to SD rats. Discussion: The findings suggest that the SD strain learns faster, but is more susceptible to depression after isolation compared to the WIS strain. Increased Co and Cu levels in ISO-SD align with previous findings, indicating potential trace element involvement in stress responses. Understanding these mechanisms could pave the way for preventive treatment strategies or therapeutic targets against the consequences of stressors, contributing to research and measures promoting a balanced diet to mitigate neurobehavioral abnormalities associated with social isolation in the future. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to propose a candidate animal model of absence status epilepticus induced by specific alpha‐2a adrenergic receptor (α2AR) activation. We also aim to investigate the responsiveness of this model to classical anti‐status or anti‐absence medications. Methods: An α2AR agonist, dexmedetomidine (DEX), was injected intracerebroventricularly into adult rats with genetic absence epilepsy, and their electroencephalography (EEG) was recorded. The total duration, number, and mean duration of each spike‐and‐wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as the initial and second sets of absence statuses. Ethosuximide (ETX) was administered as a pretreatment to another group of rats and later injected with 2.5 μg DEX. In addition, ETX, valproic acid (VPA), diazepam (DIAZ), and atipamezole (ATI) were administered after induced status‐like events following DEX administration. Power spectral characteristics and coherence analysis were performed on the EEG to assess the absence status events and sleep. Results: The 2.5 μg dose of DEX increased the total SWD duration and induced continuous SWDs up to 26 min. Following the initial absence status event, sleep was induced; then, the second period of absence status‐like activities were initiated. ETX pretreatment blocked the occurrence of absence status‐like activities. Power spectral density analyses revealed that DEX‐induced post‐sleep activities had higher power in delta frequency band (1–4 Hz) and attenuated power of 7 Hz harmonics (14 and 21 Hz) than the pre‐injection seizure. The mean duration of SWDs were decreased in all the groups, but occasional prolonged activities were seen in ETX or VPA‐injected rats but not with DIAZ or ATI. Significance: This study presents an absence status epilepticus animal model that is activated by α2AR activation to investigate the pathophysiological role of absence status. Unlike other agents ATI switched off the second set of absence statuses to normal SWDs, without sedation or lethargy, can show it may preferentially block absence status‐like activity. The Plain Language Summary: This study proposes a rat model for prolonged seizures, resembling absence status epilepticus. Activating the brain's alpha‐2a adrenergic receptor with dexmedetomidine induced seizures lasting up to 26 minutes. Ethosuximide pretreatment and post‐treatment with valproic acid, diazepam, and atipamezole decreased induced seizures. The findings suggest this model is valuable for studying absence status epilepticus. In addition, atipamezole normalized abnormal seizures without sedation, hinting at its potential for targeted treatment and further research. [ABSTRACT FROM AUTHOR]

Copyright of Acibadem Saglik Bilimleri Dergisi is the property of Acibadem University Medical School and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this article, we test the hypothesis that beliefs about the ideal mother are convergent across cultures and that these beliefs overlap considerably with attachment theory's notion of the sensitive mother. In a sample including 26 cultural groups from 15 countries around the globe, 751 mothers sorted the Maternal Behavior Q-Set to reflect their ideas about the ideal mother. The results show strong convergence between maternal beliefs about the ideal mother and attachment theory's description of the sensitive mother across groups. Cultural group membership significantly predicted variations in maternal sensitivity belief scores, but this effect was substantially accounted for by group variations in socio-demographic factors. Mothers living in rural versus urban areas, with a low family income, and with more children, were less likely to describe the ideal mother as highly sensitive. Cultural group membership did remain a significant predictor of variations in maternal sensitivity belief scores above and beyond socio-demographic predictors. The findings are discussed in terms of the universal and culture-specific aspects of the sensitivity construct.

Introduction: The genetic absence epilepsy rat from Strasbourg (GAERS) is a rat model for infantile absence epilepsy with spike-and-wave discharges (SWDs). This study aimed to investigate the potential of alpha 2A agonism to induce seizures during the pre-epileptic period in GAERS rats. Methods: Stereotaxic surgery was performed on male pups and adult GAERS rats to implant recording electrodes in the frontoparietal cortices (right/left) under anesthesia (PN23-26). Following the recovery period, pup GAERS rats were subjected to electroencephalography (EEG) recordings for 2h. Before the injections, pup epileptiform activity was examined using baseline EEG data. Dexmedetomidine was acutely administered at 0.6 mg/kg to pup GAERS rats 2-3 days after the surgery and once during the post-natal (PN) days 25-29. Epileptiform activities before injections triggered unilateral SWDs and induced sleep durations, and power spectral density was evaluated based on EEG traces. Results: The most prominent finding of this study is that unilateral SWD-like activities were induced in 47% of the animals with the intraperitoneal dexmedetomidine injection. The baseline EEGs of pup GAERS rats had no SWDs as expected since they are in the pre-epileptic period but showed low-amplitude non-rhythmic epileptiform activity. There was no difference in the duration of epileptiform activities between the basal EEG groups and DEX-injected unilateral SWD-like-exhibiting and non-SWD-like activities groups; however, the sleep duration of the unilateral SWD-like-exhibiting group was shorter. Power spectrum density (PSD) results revealed that the 1.75-Hz power in the left hemisphere peaks significantly higher than in the right. Discussion: As anticipated, pup GAERS rats in the pre-epileptic stage showed no SWDs. Nevertheless, they exhibited sporadic epileptiform activities. Specifically, dexmedetomidine induced SWD-like activities solely within the left hemisphere. These observations imply that absence seizures might originate unilaterally in the left cortex due to α2AAR agonism. Additional research is necessary to explore the precise cortical focal point of this activity. [ABSTRACT FROM AUTHOR]

Objective: Valproate (VPA) and levetiracetam (LEV) are frequently prescribed for the management of idiopathic generalized seizures; however, their welldocumented teratogenic effects raise concerns when administered to pregnant epileptic patients. This study aimed to assess the impact of VPA and LEV exposure during pregnancy on Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Methods: Female GAERS rats were categorized into three groups: saline-treated (n=6), VPA-treated (200 mg/kg, n=4), and LEV-treated (50 mg/kg, n=6). Intraperitoneal injections were initiated from mating start and continued until partition. Locomotor activity and anxiety-like behavior were evaluated using openfield and hole-board tests for the VPA-treated and VPA- and LEV-treated groups; respectively. These tests were conducted both before and during pregnancy. Results: Across all groups, open-field testing demonstrated a tendency toward reduced locomotor activity parameters compared with pre-pregnancy, with VPA treatment showing significance (p<0.05). The hole-board test indicated a trend toward decreased rearing and hole exploration, coupled with increased freezing behavior in the saline- and VPA-treated groups. The LEV-treated group showed an elevation in freezing behavior and a decline in hole exploration. Conclusion: Although minimal effects on anxiety-like behaviors were noted in anti-seizure drug-treated rats, subtle tendencies were evident in the holeboard test. VPA and LEV administration resulted in depressive parameters in the locomotor activity test. These findings emphasize the need for caution when prescribing and using VPA and the LEV during pregnancy in terms of maternal behavior and mood. [ABSTRACT FROM AUTHOR]

Introduction: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents of Ih and absence epilepsy seizures are associated, but studies reveal differential results. Objective: In our study, we aimed to investigate the role of the HCN channels on the expression of spike-and-wave discharges (SWDs) using the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Methods: HCN isoform levels from isolated brains of both naïve nonepileptic Wistar and GAERS groups were evaluated by enzyme-linked immunosorbent assay. ZD7288, an Ih inhibitor as well as an HCN channel antagonist, was administered intracerebroventricularly to the adult GAERS groups, and to evaluate their SWD activities, electroencephalography was recorded. The effect of ZD7288 on the cumulative total duration and number of SWDs and the mean duration of each SWD complex was evaluated. Results: The HCN2 levels in the cortex and hippocampus of the GAERS group were lower compared to the naïve nonepileptic Wistar group (p < 0.05). ZD7288 increased the number of SWDs at the 20th and 120th min with the highest administered dose of 7 μg (p < 0.05). Conclusion: The Ih inhibitor ZD7288 increased the number of SWDs in a genetic absence epilepsy rat model, although this increase may not be significant due to the inconsistent time-dependent effects. In GAERS, the cortical and hippocampal HCN2 channel levels were significantly lower compared to the control group. Further studies are needed with higher doses of ZD7288 to determine if the effects will increase drastically. [ABSTRACT FROM AUTHOR]

In this study, it was aimed to investigate possible ameliorating effects of thymoquinone on testicular damage in an epilepsy model. Adult male Wistar rats were divided into 4 groups. The animals in sham‐operated groups were given saline or thymoquinone (s.c.); and the animals in pentylenetetrazole (PTZ) group were applied PTZ. The animals in PTZ+thymoquinone group were given thymoquinone (i.p) for 6 days after applying PTZ. Hematoxylin‐eosin, periodic acid–Schiff and TUNEL staining and PCNA, StAR, inhibin β‐B immunohistochemistry and ZO‐1 immunofluorescence methods were applied. Staining intensity and cell numbers were determined. Degeneration of seminiferous tubules was observed in PTZ group. Most of the tubules showed normal morphology in the PTZ+thymoquinone group. Apoptotic cell index was found to be increased and proliferative index decreased in PTZ group. Thymoquinone administration decreased apoptotic index and increased proliferation index. In PTZ group, ZO‐1, StAR and inhibin β‐B immunohistochemical staining intensity was observed to be decreased and after thymoquinone application, ZO‐1 was increased. StAR and inhibin β‐B‐positive cell numbers were decreased in PTZ group and increased in the PTZ +thymoquinone group. In this study, it was observed that PTZ‐induced epileptic seizures caused testicular damage in the rat and thymoquinone ameliorated these effects. [ABSTRACT FROM AUTHOR]

Objective: The role of α2A adrenergic receptors (α2AARs) in absence epilepsy is not well characterized. Therefore, we investigated the outcomes of the specific antagonism of α2AARs on the spike‐and‐wave discharges (SWDs) in genetic absence epilepsy rats from Strasbourg (GAERSs), together with its influence on the behavior and second messenger systems, which may point to the mechanisms to which a possible SWD modulation can be related. Methods: Atipamezole, an α2AAR antagonist, was administered intracerebroventricularly to the adult GAERSs, and electroencephalography (EEG) was conducted. The cumulative duration and number of SWDs, and the mean duration of each SWD complex were counted. The relative power of the EEG frequency bands and behavioral activity after the acute application of two doses (12 and 31 μg/5 μL) of atipamezole were evaluated. The levels of cyclic adenosine monophosphate and calcium/calmodulin‐dependent kinase II (CaMKII) were measured in the cortex, thalamus, and hippocampus of naive Wistar rats and GAERSs, administered with artificial cerebrospinal fluid (aCSF) as a vehicle, or either acute or chronic atipamezole (12 μg), the latter being administered for 5 consecutive days. Results: Atipamezole significantly suppressed SWDs dose‐dependently, without affecting the relative power values of EEG frequency spectrum. The stereotypic activity was significantly lower in both naive Wistar rats and GAERSs receiving the highest dose (31 μg) of atipamezole compared to GAERSs receiving aCSF. In GAERSs, CaMKII levels were found to be higher in the thalamus after the acute and chronic application of SWD‐suppressing doses of atipamezole (12 and 31 μg) compared to aCSF. Significance: This study emphasizes the α2AR‐related modulation of absence epilepsy and particularly the significance of α2AR antagonism in suppressing SWDs. Atipamezole's SWD‐suppressive actions may be through CaMKII‐mediated second messenger systems in the thalamus. [ABSTRACT FROM AUTHOR]

Objective: Dexmedetomidine induces a two-phase of events: an initial period of absence status-like activity followed by sleep, then an immediate switch from sleep to the second period of absence status-like events (Yavuz et al, 2022). We aim to explore the effects of the de-activation of 2AR by atipamezole on these state transitions induced by dexmedetomidine in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Methods: Specific a2AR agonist, dexmedetomidine (2.5 µg), was administered via intracerebroventricular injection to adult GAERS (n=8) to induce absence status-like events. When the initial absence status-like events were triggered, atipamezole (1 mg/kg) was injected intraperitoneally. Electroencephalography (EEG) recordings were obtained 30 min before the initial administration of dexmedetomidine and 2 hours after atipamezole. The duration of SWDs and prolonged SWDs; we defined as absence status-like activities and the anesthesia sleep between were analyzed. Results: Following dexmedetomidine injection in adult GAERS, initial absence status-like activity with duration of 128±13.74 min that abruptly converts to a sleep-anesthesia was triggered. When the 31.43±2.53 long sleep anesthesia was over, it abruptly switched to prolonged chain of SWDs in 100% of the animals. Atipamezole suppressed the prolonged seizure activities for 120 min and no activity above 1 min has been observed in the EEGs (p<0.01). SWDs with a duration of 10-16 sec still occurred with atipamezole. The mean duration at the 140th min of SWDs with atipamezole (15.2±3.8; n=4) was similar to the control groups of naïve GAERS: (14.2±1.8; n=4), which SWDs are expressed spontaneously. Conclusion: Activation of a2AR triggered a switch mechanism between prolonged SWDs, anesthesia sleep, and subsequent return to SWDs, but atipamezole recovered sleep activity as expected as well as absence status by removing two phase of events. This finding provides evidence that a2AR receptor targets may be the switch mechanism between the sleep and SWDs. [ABSTRACT FROM AUTHOR]

Objectives: Rho/Rho-kinase (ROCK) signaling has been shown to contribute to neuroinflammation, epileptogenesis, and seizures in convulsivetype epilepsy models. However, this pathway has not been investigated in the pathophysiology of absence epilepsy. The aim of this study was to investigate ROCK activity in brain regions involved in spike-and-wave discharge (SWD) generation and the effects of the Rho-kinase inhibitor, Y-27632, on ROCK activity in genetic absence epilepsy rats from Strasburg (GAERS). Methods: ROCK activity in the somatosensorial cortex, hippocampus, and thalamus was measured using an enzyme-linked immunosorbent assay (ELISA). An intracerebroventricular (i.c.v.) injection of Y-27632 was administered at a dose of 20 nmol/5 µl and changes in ROCK activity were assessed. To evaluate the effect of Y-27632 on SWDs, i.c.v. 20 nmol and 60 nmol doses of Y-27632 were administered to the GAERS subjects and electroencephalography was performed. Results: ROCK activity was elevated in the somatosensory cortex in the GAERS study subjects, and the Rho-kinase enzyme inhibitor, Y-27632, suppressed this increase. In addition, Y-27632 significantly reduced the total and mean duration of SWDs compared with the control group. Conclusion: The findings indicate that the Rho-kinase pathway may play a role in the generation of absence seizures, and that the suppressive effect of Y-27632 on SWDs may be a potential therapeutic target for this anti-absent effect. [ABSTRACT FROM AUTHOR]

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels participate in pacemaker currents, modulating the funny current (I[f ]) in cardiac cells and the hyperpolarization-activated current (I[h]) in neurons. Depending on the neuronal and synaptic localization, HCN channels regulate synaptic integration, long-term potentiation, synaptic transmission, and resting membrane potential. In summary, it contributes to the electrical activity between the excitatory and inhibitory stimuli through its shunting effect. Several second messengers modulate I(h) currents in the synapses by changing voltage-dependent activation kinetics. I(h) currents are being investigated in numerous central nervous system disorders, including epilepsy. On one hand, it is well known that I(h) currents lead to synchronized oscillations in the rhythmic burst mode in thalamocortical neurons underlying the pathophysiology of absence epilepsy. However, much of the evidence is contradictory. Therefore, it is important to understand the dynamic relationship of HCN channels within the oscillatory networks to determine the regional "queerness" of I(h), and we need further investigation to determine if upregulation or downregulation of I(h) is needed in order to suppress seizure activity. [ABSTRACT FROM AUTHOR]

Objective: 6-Hydroxydopamine (6-OHDA) is a toxic agent for the nigro-striatal dopaminergic neurons and it is used in modeling Parkinson's disease in rats (1). It is aimed to compare in genetic absence epilepsy rats (GAERS) and Wistar rats from Strasbourg, the apomorphine-induced rotation behavior, which is one of the indicators of dopaminergic damage of 6-OHDA toxicity. Methods: In this study, 30 days old Wistar and GAERS animals were divided into two groups. 6-OHDA(8 pg dose and 4 pL/4 minutes) was injected by stereotaxic surgery into the medial forebrain bundle (MFB) (AP: -1.4; ML: 1.6; V: 7.1 mm; single injection) of GAERS-MFB group (n=8), into the striatum (AP:-O.5/+O.5; ML:3.0; V: 5.0 mm; double injections) of GAERS-Striatum group (n=5), as well as into the MFB (AP:-1.4; ML: 1.6; V: 7.1 mm; single injection) of Wistar-MFB group (n=4) and the striatum (AP: -O.5/+O.5; ML: 3.0; V: 5.0 min; double injections) of Wistar-Striatum (n=2) group. After 21 days, all animals were injected with apomorphine (0.05 mg/kg, subcutan). After apomorphine administration, right and left rotation (3600) of the animals were recorded for 30 minutes. Data were expressed as mean+standart error. One-way ANOVA and Tukey post-hoc test were used (p<0.05 was considered significant). Results: The mean number of GAERS-MFB rotations was 6.56±0.05 per minute, whereas the GAERS-Striatum was 6.19±1.72 per minute. While the number of Wistar-MFB rotations was 4.74+2.33 per minute, the number of Wistar-Striatum rotations was 3.27±1.40 per minute. There was no statistically significant difference between the groups. Conclusion: Although the findings show there is no difference between the groups, it is aimed to continue the study by increasing the number because of the numbers of groups are limited in our study. The study is supported by TÜBİTAK (218S653). [ABSTRACT FROM AUTHOR]

Objective: Valproate is a well-recognized therapeutic choice in the management of epilepsies and manic episodes of bipolar disorders and has been associated with Parkinson-like symptoms, especially tremor, when used for long-term. Despite being reported as often resolved upon drug discontinuance, the symptoms might be permanent. This study aimed to determine whether a five-day administration of valproate resulted in the development of a Parkinsonism model in Wistar rats. Methods: Twice daily valproate 400 mg/kg were intraperitoneally injected to adult male Wistar rats (n=6) for five days. Locomotor, stepping, paw reaching, cylinder, and tremulous jaw movement tests were applied three days before the injection and at the end of the last valproate administration. Tremor data scoring is as follows: 0: no tremor, I: intermittent tremor, affecting only head and neck,II: intermittent tremor, affecting whole body, III: continuous tremor affecting whole body, tail, IV: continuous tremor Results: Tremulous jaw movement stage II and I occurred in 60% and 40% of rats, respectively; while no rats developed stage III or IV tremor upon 5-day course of valproate. There were sıgnificant reduction in total distance (%53.8 p<0.05), vertical and horizontal movements and in ambulatory time (%77.2, p<0.05; %48.64, p<0.05 and %52,3, p<0.05 respectively) compared to baseline in the locomotor activity test. While the number of stepping at the right side was significantly lower compared to the baseline (p<0.05). Cylinder test scores at minutes 0-2 significantly decreased in the right side by %93.4 and in the left side by %90,5 at the end of the study (p<0.05). Conclusion: The findings of the locomotor and cylinder tests imply that a five-day administration of valproate might elicit the development of a rat Parkinsonism model which appears to be substantially consistent with those in the literature. Our study, with dose and time modifications, can provide source for new researches. [ABSTRACT FROM AUTHOR]

Objective: The most common type of epilepsy affecting about 50 million people worldwide is temporal lobe epilepsy (TLE). Chemical and electrical kindling methods in animals can be used to form the TLE model. In this study, it was aimed to investigate neurogenesis by immunofluorescence methods in the hippocampus of adult Wistar rats, which were applied chemical kindling. Methods: Adult male Wistar albino rats weighing 250-300 gr were injected PTZ (35 mg/kg) subcutaneously every other day to produce chemical kindling (Wistar kindling 7th day group n=6; 14th day group n=6). Sham-operated control groups were injected physiological saline solution subcutaneously (Wistar shamoperated 7th day group n=6; 14th day group n=6). Animals having grade 5 seizures five times were considered to be kindled. Intracardiac perfusion was performed under deep anesthesia on the 7th and 14th days after the last grade 5 seizure. Then, the animals were decapitated and brain tissues were removed and incubated at 4°C overnight within the same fixative. The tissues were frozen at -80ºC and 5 μm sections were obtained with a cryomicrotome. Immunofluorescence methods were used to show doublecortin (DCX) positive newly formed neurons and glial fibrillary acidic protein (GFAP) positive cells. Sections were then examined under fluorescence microscope. Results: DCX positive cells were observed in the subgranular zone of gyrus dentatus in the control and kindling groups. An increase in GFAP positive cells in the kindling groups, compared to the control groups, was observed. Conclusion: The findings of the present study indicate the existence of neurogenesis in the control and kindled adult Wistar rats. The increase in GFAP positive cells in the kindling groups suggests astrogliosis. [ABSTRACT FROM AUTHOR]

Analyses of the present data are reported in the article "Crossing Boundaries: A Pilot Study of Maternal Attitudes about Child Maltreatment in Nine Countries" [8]. Data were collected during home visits using the Maltreatment Q-Sort (MQS). A total of 466 mothers from nine different countries gave their opinion about child maltreatment by sorting 90 cards with parenting behaviors taken from the literature that reflect four types of child maltreatment, into 9 evenly distributed stacks (with 10 cards each) from least to most harmful for the child. This data article provides an overview of the content of the 90 items, which type of maltreatment they reflect, and the source of the items. The percentage of mothers labelling each of the MQS items as maltreatment is also presented. In addition, instructions are included about the administration of the MQS as well as data-entry and analyses of Q-sort data, accompanied by example datasets and syntaxes. This can serve as a manual for researchers interested in using Q-sort data., (© 2020 The Author(s).)