Papers by Jana Tchekalarova
Background Aging affects anxiety levels in rats while the pineal gland, via its hormone melatonin... more 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. Both 18-month-old sham- and rats with pinealectomy exhibited impaired circadian variations of motor activity. 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, l...
Dokladi na Bʺlgarskata akademiâ na naukite, Oct 30, 2023
Exogenous treatment during pregnancy with steroid hormones (estrogens, androgens, or glucocortico... more Exogenous treatment during pregnancy with steroid hormones (estrogens, androgens, or glucocorticoids) affects the development of the fetus and the sexually mature generation. In clinical practice, the hormone progesterone is used therapeutically in programmes for assisted reproduction, infertility treatment, threatened abortion and premature birth. The hormone has a key role in establishing and maintaining pregnancy through its endocrine and immunological effects. Despite the fact that progesterone is widely used during pregnancy, the long-term effects of fetal exposure to exogenous progesterone on child development have barely been investigated. The aim of the present study is to investigate sex-dependent changes in the emotional status of a generation of prenatally treated with progesterone offspring. Female pregnant rats were treated subcutaneously with progesterone (50 mg/kg) from gestational (G) period G0 to G10. Anxiety and depressive-like behaviour of male and female adult offspring were evaluated with an open field (OF) test, elevated plus maze test (EPM), light dark test (LDT), sucrose preference test (SPT) and forced swimming test (FST). Prenatal treated with progesterone male and female offspring exhibited lower horizontal and vertical activity compared to the male and female control rats in the open field test and decreased distance and time spent in the open
International Journal of Molecular Sciences
Recently, the four 5,5′-diphenylhydantoin Schiff bases, possessing different aromatic species (SB... more 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 cis SB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cis SB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cis SB1-Ph compound and the cis SB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to...
Amino Acids, Jan 3, 2022
In the present study, a series of new analogues of both LVV- and VV-hemorphin-7 have been synthes... more In the present study, a series of new analogues of both LVV- and VV-hemorphin-7 have been synthesized and characterized. They were modified at the N- and C-terminus with varied amino acids (Ile, D-Leu, D-Val, D-Phe) and enantiopure chiral S- and R- α-aminophosphonic acids ((dimethoxyphosphoryl)methyl)-valine and ((dimethoxyphosphoryl) methyl)-leucine) to optimize the physicochemical properties and to enhance their anticonvulsant potency. The novel peptide analogues were prepared by solid-phase peptide synthesis-Fmoc-strategy. Their structure-property relationship was studied by FT-IR spectroscopy and electrochemical methods. The lipophilicity is also presented. The anticonvulsant activity of peptide analogues, administered intracerebroventricularly, at doses of 1, 2.5, and 5 μg/10 μL, respectively, was explored by 6-Hz psychomotor seizure test, maximal electroshock test (MES) and a timed intravenous pentylenetetrazole (ivPTZ) infusion test in mice. The potential neurological toxicity of the substances was checked by a rotarod test. The H7 was used as a positive control. The H7-1 peptide analogue was the most active molecule against the psychomotor seizures, while H7-6 and H7-7 showed comparable to the positive group H7 potency in the MES test. The H7-5 to H7-8 analogues at the two tested doses of 2.5 and 5 μg/10 μl raised the threshold against ivPTZ-induced myoclonic, clonic, and tonic seizures. None of the hemorphin analogues exhibited neurotoxicity in the rotarod test. In conclusion, our results suggest that modified at N- and C-terminus of certain amino acids in the hemorphin analogues have a crucial role as a basis to design new LVV- and VV-hemorphin-7 analogues for experimental and clinical use.
Seizure-european Journal of Epilepsy, Apr 1, 2018
Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance bot... more Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy. Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist b-caryophyllene (BCP) in models of seizures and cognition in mice. Methods: Dose-dependent effects of BCP was studied in maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test and Morris water maze test. Phenytoin and diazepam were used as reference drugs in seizure tests. The effect of sub-chronic treatment with BCP for 7 days (50 and 100 mg kg À1) was assessed on status epilepticus (SE) induced by kainic acid (KA) model and oxidative stress through measurement of malondialdehyde (MDA) level in the hippocampus. The acute neurotoxicity was determined by a rotarod test. Results: The BCP exerted a protection in the MES test at the lowest dose of 30 mg kg À1 at the 4-h interval tested comparable to that of the referent drug phenytoin. The CB2 agonist was ineffective in the scPTZ test. The BCP displayed no neurotoxicity in the rotarod test. The BCP decreased the seizure scores in the KA-induced SE, which effect correlated with a diminished lipid peroxidation. The CB2 agonist exerted a dose-dependent decrease of latency to cross the target area during the three days of testing in the Morris water maze test. Conclusion: Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.
Physiology & Behavior, Oct 1, 2023
Amino Acids, Jan 2, 2019
A novel analog of VV-hemorphin-5 containing azobenzene moiety has been synthesized and investigat... more A novel analog of VV-hemorphin-5 containing azobenzene moiety has been synthesized and investigated for anticonvulsant activity in relation to its E → Z photophysical properties activated by long wavelength light at 365 nm. The synthesis was achieved by a modified SPPS by Fmoc-dimerization strategy. The electrochemical behavior before and after UV illumination was investigated using different voltammetric modes. The number of electrons transferred, heterogenic rate constant and diffusion coefficient for E- and Z-isomers were also evaluated. Revealing the governing principles involved in signaling and nerve pulse propagation requires the detailed characterization of the electrical properties of cell membranes. For probing the effect of synthesized azo-peptide on the membrane electrical properties, we measured the specific capacitance of lipid bilayers, representing a basic physical model of biomembranes with their simple reproducibility in laboratory conditions at controlled membrane composition and physicochemical parameters of the surrounding aqueous medium. Our results have shown reduced membrane capacitance in the presence of the azo-peptide, thus providing evidences for possible alterations in the dielectric permittivity of the bilayer. The (Val-Val-Tyr-Pro-Trp-Thr-Gln)2Azo peptide was explored also in vivo for preliminary anticonvulsant activity by using the 6-Hz seizure test and pentylenetetrazol (PTZ) seizure test in mice. The Z-isomer has exhibited higher potency compared to E-isomer most pronouncedly in the 6 Hz test for psychomotor seizures where the compound had activity at all three tested doses. It was found that the Z-isomer decrease the latency for onset of clonic seizures induced by PTZ. These results demonstrate that the Z-isomer deserves further evaluation in other screening tests for anticonvulsant activity.
International Journal of Molecular Sciences, Oct 29, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences, Sep 8, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Canadian Journal of Physiology and Pharmacology, May 1, 2018
Cumulative data suggest the significant role of the Renin-Angiotensin System in the development o... more Cumulative data suggest the significant role of the Renin-Angiotensin System in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of a peptide AT2 agonist Novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1 DM) in Wistar rats. Food and water consumption, body weight, urine excretion (metabolic cages), motor activity (open field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test) and plasma levels of glucose and corticosterone (ELISA) were assessed two weeks after the T1 DM induction. Novokinin increased water and food consumption, and urine output and reduced weight gain in the control rats. Diabetic rats demonstrated hyperalgesia, increased level of plasma corticosterone, decreased motor and exploratory activity, impaired spatial memory. Novokinin infusion increased water intake, diuresis and mortality rate, decreased food intake, exacerbated diabetes-induced hyperalgesia and provoked anxiety-like behavior but improved spatial memory in diabetic rats. These initial data suggest that angiotensin AT2 receptors participate in the pathogenesis of T1 DM-induced complications in the function of the nervous system.
Pharmaceuticals, Oct 11, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Methods and Findings in Experimental and Clinical Pharmacology, 1998
The present study was undertaken to further evaluate the effects of angiotensinergic agents: angi... more The present study was undertaken to further evaluate the effects of angiotensinergic agents: angiotensin II (AII), its analogues sarmesin ([Sar1, Tyr(Me)4]AII) and sarilesin ([Sar1, Ile8]AII), as well as DuP 753, a nonpeptide selective AT1 receptor antagonist, on apomorphine stereotypy in rats thus providing further evidence for AII-DAergic receptor interactions. All drugs were administered intracerebroventricularly (i.c.v.). Stereotyped behavior was evoked by an i.p. injection of 3 mg/kg apomorphine. AII (0.1-5 micrograms) exerted a decrease on stereotypies (U-shaped); the effect being significant at doses of 1 and 2 micrograms. Sarmesin significantly increased apomorphine stereotypy at a dose of 5 micrograms and decreased it at a dose of 20 micrograms. Sarmesin (10 micrograms) reversed the decreasing effect of AII (2 micrograms) leading to a more pronounced increase of stereotypies. Sarilesin (5 micrograms), which by itself is inactive, also demonstrated antagonistic properties when injected 5 min before AII (2 micrograms). DuP 753 (100 micrograms) alone had no significant effect on apomorphine stereotypy, but injected 5 min before AII (2 micrograms) it reversed the decreasing effect of AII on stereotypy. Taken together, the results further confirm the hypothesis that AII closely interacts with DAergic neurotransmission, an effect which is mediated predominantly by AT1 receptors.
Pharmaceuticals, Nov 17, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Brain Research, Nov 1, 2015
The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depress... more The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a
International Journal of Molecular Sciences, Jul 12, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences, Jan 9, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Biomedicine & Pharmacotherapy, Oct 1, 2018
Epilepsy is a neurological disease affecting people of all ages worldwide. Side effects of antiep... more Epilepsy is a neurological disease affecting people of all ages worldwide. Side effects of antiepileptic drugs and their association with oxidative stress stimulate the search for new drugs, which would be more affordable with fewer adverse effects. Accordingly, the aim of the present work is to evaluate the anticonvulsant effect of anacardic acid (AA), a natural compound extracted from cashew liquid (Anacardium occidentalis), in murine models, as well as its antioxidant actions in Saccharomyces cerevisiae. AA (> 90% purity) was tested, in vivo, in male Swiss mice (25-30 g) with four convulsive models, (1) pentylenetetrazole, (2) pilocarpine, (3) electroshock, and (4) kainic acid, at doses of 25, 50, and 100 mg/kg, body weight (B.W.) Additionally, the effective dose, toxic dose, and protective index studies were also performed. Results revealed that AA exhibits anticonvulsive effects in models 1, 3, and 4, with a mean effective dose (ED 50) of 39.64 (model 1) > 100 mg/kg, B.W. (model 2), and
Archiv der Pharmazie
Two series of new VV‐hemorphin‐5 analogs with structures Val–Val–Tyr–Xxx–Trp–Thr–Gln–NH2 and Adam... more 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. Th...
Journal of Pharmaceutical Sciences
The Neuroscience of Depression, 2021
Abstract Depression, concomitant with epilepsy, may cause serious impairment in one’s quality of ... more Abstract Depression, concomitant with epilepsy, may cause serious impairment in one’s quality of life, not limited to seizures. Investigations of biomarkers and new therapeutic approaches targeting comorbid depression in epilepsy have been in progress for the past decade. In the attempt to find the mechanisms underlying the development of depression in epilepsy, an important part of the research is devoted to elucidating what the precise impact of inflammatory mediators is. Here, we overview the role of critical inflammatory pathways involved in the development of depression comorbid to epilepsy. The scarcity of evidence in literaure that has contributed to the elaboration of the hypothesis for a common and specific inflammatory signaling mechanism responsible for the generation of depressive state in epilepsy is discussed. In addition, the possibility of the implementation of suitable antiinflammatory therapies suggested to ameliorate depression accompanying epilepsy is analyzed.
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Papers by Jana Tchekalarova