Anti-depressant Activity of Carboxylate Derivatives for the treatment of Corticosterone and Lipopolysaccharide-induced depression in mice model
Amit Kumar Sharma1, Vikramdeep Monga2, Tanveer Naved1*
1Amity Institute of Pharmacy, Amity University, Noida Campus, Uttar Pradesh, India – 201313.
2Department of Pharmaceutical Sciences and Natural Products,
Central University of Punjab, Ghudda, Bathinda, Punjab, India -151401.
*Corresponding Author E-mail: tnaved@amity.edu
ABSTRACT:
The objectives of present investigation include the evaluation of antidepressant activity of two hit compounds identified using in silico approach i.e. molecular docking. The identified hit compounds JC-41 and JC-42 exhibited depressive-like behavior caused by Corticosterone and LPS in mice model. The behavioral activities were evaluated for these two compounds by using open-field tail suspension (TST) and forced swimming (FST) tests. In addition, biochemical markers such as reduced glutathione, monoamine oxidase, corticosterone, malondialdehyde, and nitric oxide levels were examined in serum. The results demonstrated that the compounds JC-41 and JC-42 significantly improved the behavioral activity as well as the metabolic parameters in the treated mice with depression. Both the compounds demonstrated significant antidepressant activity; however, JC-42 exhibited a superior response as compared to JC-41. To summarize, the results of the present study highlighted that both the compounds elevate symptoms resembling depression by diminishing oxidative stress and decreasing the levels of corticosterone and monoamine oxidase-A (MAO-A).
KEYWORDS: Depression, Corticosterone, Antidepressant, MAO-A, LPS, Docking.
INTRODUCTION:
Despite variability in prevalence estimates across countries, socio-demographic correlates and adverse effects of major depression are consistently found. Corticosteroids, released after stress-induced HPA axis activation, maintain homeostasis but can cause brain damage under pathological conditions with high glucocorticoid levels, leading to decreased hippocampal neurogenesis and dendritic branching4–7. Stress is a key trigger for depression, with patients often exhibiting hypercortisolemia. Chronic CORT treatment in animals replicates depressive symptoms such as increased immobility, decreased grooming, anxiety-like behaviors and anhedonia. Similarly, administration of lipopolysaccharide (LPS) with a single injection induces depression model associated with inflammation, characterized by behavioral alterations such as reduced preference for sucrose and heightened feelings of despair. This model is linked to increased levels of pro-inflammatory cytokines and lower levels of BDNF in prefrontal cortex (PFC) and hippocampus, higher corticosterone and modified monoamines. Antidepressant medications can reverse all of these effects8–10,11-12.
MATERIAL AND METHODS:
Material:
All compounds used for the investigation were of analytical grade and procured from reputable companies. The test kits were procured from Sigma Aldrich, Japan.
Methods:
Approach for the synthesis of substituted oxadiazole derivatives:
Place 5-(4-substituted aryl)-1,3,4-oxadiazole-2-thiol (1 mmol), p-nitrobenzyl bromide (1mmol) and sodium hydroxide (5mmol) in ethanol (10mL) and stirred the contents at room temperature. The completion of reaction was monitored by thin layer chromatography. After completion, the reaction mixture was concentrated and poured in ice cold water, wherein the crude product was precipitated out. The precipitates thus obtained were filtered, thoroughly washed with water, dried and recrystallized from aqueous methanol to get pure product JC-41 in good yield (63%). A mixture containing equimolar quantity of 2,4-dicholrobenzhydrazide and methyl-2-oxo-1,2-dihydroquinolone-3-carbaldehyde in absolute ethanol was refluxed in the presence of few drops of glacial acetic acid for 6 hrs. After the completion of reaction, the resulting mixture was poured into ice and solid thus obtained was filtered, washed with water, dried and further purified by recrystallization from ethanol to get the required intermediate hydrazine derivative. A solution of hydrazone derivative (500mg) in acetic anhydride (4mL) was refluxed for 6 hrs. Upon completion of the reaction as monitored by TLC, the reaction medium was poured into cold water. The precipitates thus obtained were filtered, thoroughly washed with water, dried and the crude product was purified by column chromatography using chloroform: methanol as the mobile phase to get the pure product JC-42 in good yield (58%).
Experimental Design
In house library of oxadiazole derivatives were subjected to molecular docking against MAO–A enzyme. The crystal structure of the MAO-A co-crystallized with clorgyline inhibitor was downloaded from the Protein Data Bank (PDB ID: 2BXR, 1BND and 2Z5X). Docking calculations were performed to predict the binding affinities of various compounds and proteins of interest 2BXR, 1BND and 2Z5X by using AutoDock 4.2 tool. The generated maps were calculated by using the auxiliary program AutoGrid. Molecular docking study and MMGBSA binding free energy revealed that the maximum binding energy was calculated and the generated scores lead to identification of two hit compounds JC-41 and JC-42 which were used for further studies. These compounds with highest binding scores were then tested in vivo for antidepressant activities in mice model13. Further, pharmacological investigations were performed for these two candidates (JC-41 and JC-42) to explore their antidepressant potential using corticosterone and lipopolysaccharide models.
Corticosterone Model:
Corticosteroids are secreted due to the HPA axis is activated in reaction to stress, to maintain a stable internal environment. Nevertheless, elevated levels of glucocorticoids in pathological circumstances can lead to brain impairment, this includes a reduction in the creation of new neurons in the hippocampus and a disruption in the growth of dendrites in the CA3 and PFC areas14–16. Stress has a significant role in causing depression, often resulting in elevated levels of cortisol in individuals, a condition known as hypercortisolemia. Animal models replicate chronic stress by subjecting them to elevated amounts of glucocorticoids, leading to dysregulation of the HPA axis and behavioral alterations such as heightened immobility, reduced grooming, anxiety-like behaviors, and anhedonia4–7. Additionally, these animals demonstrate diminished hormonal stress reactions, heightened activation of stress-responsive areas in the brain, neuroinflammation, reduced levels of BDNF in hippocampus and modified serotoninergic neurotransmission. Exogenous treatment of corticosterone notably increases corticosterone levels during the dark phase, but does not affect levels during the circadian nadir. This is different from variations in corticosterone levels caused by chronic stress17,18.
Lipopolysaccharide Model:
A single injection of lipopolysaccharide (LPS) can induce an inflammation-related depression model administered at a specific therapeutic dosage range of 0.5 to 0.83 mg/kg. This model exhibits a reduction in the liking for sucrose and an elevation in despair-related behaviors. This model is linked to elevated levels of pro-inflammatory cytokines, such as IL-1β and TNF-α, in the brain. These raised levels can be reversed by antidepressant medicines. Neurobiological changes involve decreased levels of BDNF in the prefrontal cortex (PFC) and hippocampus, increased BDNF in the nucleus accumbens (NAc), elevated corticosterone, and altered monoamines in corticolimbic areas8,9,19.
Animals:
The Swiss albino mice, weighing between 15 and 20 grams, were from the Experimental Animal Centre of Amity University, located in Greater Noida. The subjects were subjected to a 12hrs alternation between periods of daylight and darkness at a controlled temperature of 23±2°C. They were given full access to regular food and water. After 1 week of adjustment, the tests were carried out with the clear approval of the Animal Ethics Committee. Attempts were undertaken to mitigate animal distress and decrease the quantity of animals utilized.
Drugs Treatment:
Mice (n=6) were divided into five groups based on weight: vehicle, CORT, CORT+JC-41 (100mg/kg), CORT+JC-42 (100mg/kg), and CORT+Moclobemide (50mg/kg). Except for the vehicle group, the mice were administered daily subcutaneous injections of CORT (20 mg/kg) at a dosage of 1 ml/kg. Standard drug and new chemical entities (NCEs) were administered orally in a 0.5% CMC-Na suspension 30 minutes before CORT injection for 21 days (Table 1).
Table 1: Study Plan of Corticosterone and LPS drug treatment administration
|
Group |
Treatment of CORT |
Treatment of LPS |
|
Group 1 (Vehicle Control) |
1 ml (0.5% CMC-Na) |
1 ml (0.5% CMC-Na) |
|
Group 2 (CORT/ LPS) |
CORT (20 mg/kg) |
LPS (0.5 mg/kg) |
|
Group 3 (Standard group) |
CORT + Moclobemide (50mg/kg) |
LPS + Moclobemide (50mg/kg) |
|
Group 4 (Test Group 1) |
CORT + JC-41 (100mg/kg) |
LPS + JC-41 (100mg/kg) |
|
Group 5 (Test Group 2) |
CORT + JC-42 (100mg/kg) |
LPS + JC-42 (100mg/kg) |
Behavioral Assessment:
a. Sucrose Preference Test (SPT):
SPT was conducted 24 hours after the final administration of medicine. Before the start of the experiment, the mice were accustomed to a 1% sugar solution for 3 days. On the 18th day, the mice underwent training using two bottles containing a solution consisting of 1% sucrose. On 19th day, a substitution was made where one bottle containing sucrose was exchanged with tap water and left for a duration of 24 hours. Before conducting SPT, the mice were deprived of food and water for 24 hours. Afterward, the mice were given access to both bottles containing nourishment and hydration. The measurement of sucrose consumption was obtained by comparing difference in weight between the bottles before and thereafter to experiment20.
The calculation of sucrose preference was performed in the following manner:
Sucrose intake (g)
Sucrose preference (%) = ––––––––––––––––––––––––––––––– × 100
(Sucrose intake (g) + water intake (g))
b. Open field test (OFT):
Random locomotor activity was measured by conducting an OFT in a square hardwood arena with dimensions of 60x40x50 cm. The floor was partitioned into 12 squares, with each mouse positioned at the midpoint. Two impartial observers documented quantity of crossings and rearings that occurred throughout a 5-minute session. During intervals between experiments, arena was thoroughly sanitized using solution of 10% ethanol to eliminate any lingering scents.
c. Forced swim test (FST):
The forced swim test was administered on the 21st day of the experiment. Each mouse was immersed in a glass vessel consisting of water at a specific temperature of 25 ±1°C for a duration of 6 minutes. The duration of immobility for the preceding 4 minutes was documented, with immobility being defined as the minimum number of movements necessary to maintain the head above water. Water was changed after every test to reduce any possible disruption21,22.
d. Tail suspension test (TST):
The TST was carried out 24hours following the forced swim test. Each mouse was elevated to a height of 50 cm above the ground by affixing adhesive tape to its tail, approximately 1 cm from the tip. The test had a duration of 6minutes, and the state of being motionless for the final 4minutes was documented. Observers were intentionally kept unaware of group assignments to reduce the influence of subjective bias20,22-24.
Collection of brain samples:
On the 21st day, animals from various groups were euthanized via decapitation. The brain tissues were expeditiously extracted and cryogenically preserved on dry ice, then preserved at a temperature of -80°C. Tissue samples were collected measured and blended in a solution of 0.9% normal saline to create a 20% homogenate. Following a rotation at a speed of 3000 revolutions per minute for a duration of 10 minutes, while being exposed to a temperature of 4°C liquid above the sediment was separated into smaller parts and stored at -80°C. Following on, these sections were used to analyze reduced glutathione (GSH), lipid peroxides (LPO), and monoamines.
Neurochemical determinations:
a. Estimation of decreased Glutathione and lipid peroxides:
The quantification of lipid peroxides (LPOs) was performed using spectrophotometry, specifically by measuring thiobarbituric acid-reactive compounds (TBARs) according to method established by Mihara and Uchiyama. The assay relies on interaction between malondialdehyde and thiobarbituric acid under certain conditions of low pH and high temperature. This reaction generates a pink-colored product that is extracted using n-butanol and subsequently quantified at a wavelength of 535nm. Brain homogenates were utilized to find the decreased level of glutathione (GSH), a naturally occurring non-enzymatic antioxidant. Proteins were separated by adding trichloroacetic acid, and the resulting mixture was spun at high speed. The liquid portion above the solid residue was collected and utilized to measure the concentration of GSH using Ellman's reagent at a wavelength of 412nm25.
b. Determination of serum corticosterone levels:
The concentration of serum corticosterone was measured using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit (CUSABIO, Wuhan, China) following the manufacturer's instructions. A calibration curve was generated by utilizing predetermined concentrations of the product, and the optical density (OD) of the solution was quantified at 450nm using a microplate spectrophotometer.
c. Effect on the 5-HT and NE levels in the hippocampus:
The levels of 5-HT and NE in the hippocampus were quantified using ELISA kits. The optical density of each well was quantified using a microplate spectrophotometer set at a wavelength of 450nm, within 5 minutes.
Statistical Analysis:
The data were displayed as the average value plus or minus the standard error of the mean (SEM). The assessment of significant differences between means was conducted using one-way analysis of variance (ANOVA) and Student's t-test with the assistance of GraphPad Prism version 5(GraphPad Software). A P-value equal to or less than 0.05 was deemed to be statistically significant.
RESULT AND DISCUSSION:
Assessment of Parameters in Corticosterone-induced depression:
a. Sucrose Preference test:
Sucrose preference over water was quantified as a proxy indicator of hedonic behavior in the SPT. There were notable disparities observed between the standard group and the test groups as compared to the CORT group. The results indicated a higher desire for sugar in the group treated with the usual medicine, Moclobemide (***p<0.001), and JC-42 (**p<0.01) compared to the other group (figure 1).
Figure 1: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Sucrose preference test in a mouse model of depression produced by Corticosterone. Values are reported as the mean ± SEM; there were 6 subjects in each group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the CORT group.
b. Effect of JC-41 and JC-42 on Open Field Test (OFT):
The consequences of JC-41 and JC-42 on locomotor activity were evaluated utilizing an open-field behavior test. The results indicated that the treatment groups receiving the standard medicine, Moclobemide (50 mg/kg), and JC-42 (100mg/kg), exhibited a substantial alteration in the number of crossings and rearings (***p<0.001 and **p<0.05, respectively) compared to the CORT group. The results were shown in the (figure 2).
a)
b)
Figure 2: The impact of JC-41 and JC-42 treatment on motor functions was evaluated using an open field test in a mouse model of Corticosterone-induced depression. The number of squares crossed (A) and number of episodes of rearing (B) were measured. The values are shown as the mean ± SEM, with a sample size of 6 per group. A statistically significant difference was observed in Moclobemide group (***p<0.001) and JC-42 group (**p<0.05) compared to the CORT group.
c. The impact of JC-41 and JC-42 on the duration of lack of movement in Forced Swim Test (FST):
The forced swim test is a direct and effective animal model employed to assess the antidepressant properties of a potential drug. According to the empirical evidence given in (figure 3), the analysis of variance (ANOVA) revealed that mice treated with CORT showed a substantial rise in the length of immobility compared to the animals treated with the vehicle. Administering the JC-42 molecule at a dosage of 100mg/kg and treating with Moclobemide significantly reduced the length of immobility compared to the CORT group (p<0.05, p<0.001, respectively).
Figure 3: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Forced Swim Test in a mouse model of depression induced by Corticosterone. The values are presented as the mean ± SEM, with a sample size of 6 per group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the CORT group.
d. Impact on the period of immobility in the Tail Suspension Test (TST):
TST is a further animal model used to assess the antidepressant concerns of potential candidates, alongside the forced swim test (FST). Based on the findings shown in (figure 4), mice that were given CORT exhibited a significant increase in the length of time they remained motionless, in comparison to the group that got the vehicle. After a consistent 21-day treatment period, the administration of Moclobemide, in combination with JC-42 at a dosage of 100 mg/kg, significantly decreased the duration of immobility as compared to the CORT group.
Figure 4: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Tail Suspension test in a mouse model of depression induced by Corticosterone. Values are reported as the mean ± SEM; there were 6 subjects in each group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the CORT group.
Collection of brain samples:
The brain tissues were gathered and preserved. A homogenate was produced and subsequently centrifuged at a speed of 3000 revolutions per minute for 10 minutes. The liquid was partitioned into smaller aliquots and stored at a temperature of -80°C for the examination of reduced glutathione (GSH), lipid peroxides (LPO), and monoamines.
Assessment of Biochemical Parameters:
a. Impact of JC-41 and JC-42 on the glutathione (GSH) levels:
The injection of corticosterone resulted in a notable reduction in GSH levels, accompanied by a large increase in TBARS (a measure of lipid peroxidation), when compared to the control group (p<0.001). This indicates an imbalance between oxidants and antioxidants. The reduction in GSH levels and increase in TBARS levels were mitigated by the administration of synthetic compounds or Moclobemide, as compared to animals treated with Cort. The administration of the compound JC-42 at a dosage of 100 mg/kg resulted in a notable enhancement in comparison to compound JC-41. The results are displayed in (figure 5).
b. Effect of JC-41 and JC-42 on brain levels of Monoamines:
Emerging research suggests that the neurotransmitters 5-HT and NE play a role in the development of depression. To evaluate the effectiveness of new chemical entities (NCEs) JC-41 and JC-42 as antidepressants, ELISA analysis was employed to quantify the levels of monoamine neurotransmitters. The mice subjected to Cort therapy for 21 days had significantly reduced levels of Serotonin and Dopamine compared to the control group. Pretreatment with either NCEs (JC-41 and JC-42) or Moclobemide mitigated the Cort-induced reduction of Serotonin and Dopamine. Preconditioning with Moclobemide and JC-42 (100 mg/kg) significantly increased the levels of Serotonin in the brain, compared to JC-41 (100 mg/kg). On the other hand, mice that were administered Cort exhibited a significantly elevated concentration of Norepinephrine in the brain as compared to the control group. Nevertheless, mice who had prior treatment with JC-42 and Moclobemide demonstrated a substantial decrease in Norepinephrine levels (p<0.05 and p<0.001, respectively) compared to mice treated with Cort. Similarly, monoamine oxidase level was increased in CORT treated group, while, it was decreased significantly, with Moclobemide (***p<0.001) and JC-42 (**p<0.05).
Figure 5: The impact of JC-41 and JC-42 administration on biochemical markers, specifically the levels of reduced glutathione (GSH) (A), thiobarbituric acid reactive substances (TBARS) (B), serotonin (5-HT) (C), and MAO (D), was evaluated in a depression model produced by corticosterone. Values are reported as mean ± SEM; there were 6 subjects in each group. A statistically significant difference was observed in the Moclobemide group (***p<0.001) and JC-42 group (**p<0.05) compared to the CORT group.
c. Effect of JC-41 and JC-42 on the Serum Corticosterone Levels
Glucocorticoids, such as cortisol in humans and corticosterone in rodents, have a significant impact on the onset of depression. The CORT concentration in the blood serum was assessed using ELISA methods. Based on the findings depicted in Figure 6, the blood CORT levels in the CORT group exhibited a considerable increase in comparison to the vehicle group. Following 21 days of treatment, both the JC-42 (100 mg/kg) and Moclobemide groups exhibited a significant reduction in blood CORT levels (p<0.05 and p<0.001, respectively).
Figure 6: The impact of JC-41 and JC-42 medication on the level of Corticosterone in a mouse model of depression produced by Corticosterone. The values are presented as the mean ± SEM, with a sample size of 6 per group. A significant difference was observed in the Moclobemide group (***p<0.001) and JC-42 group (**p<0.05) compared to the CORT group.
Assessment of parameters in LPS-induced depression in mice model:
Assessment of Behavioral Parameters:
a. Forced swimming test:
Mice in the LPS group exhibited significantly longer periods of immobility during the Forced Swim Test (FST) compared to mice in the control group. The administration of the normal medicine, Moclobemide, as well as the new chemical entities (NCEs) JC-41 and JC-42, resulted in a decrease in the amount of time the subjects remained immobile, when compared to the CORT group. More promising response was obtained with the compound JC-42 (**p<0.05), comparable to standard drug, Moclobemide (***p<0.001, figure 7).
Figure 7: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Forced Swim Test in a mouse model of depression induced by LPS. The values are presented as the mean±SEM, with a sample size of n= 6 per group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the LPS group.
b. Tail Suspension Test (TST):
The duration of immobility observed during the Tail Suspension Test (TST) was considerably longer for the mice in the LPS group compared to the mice in control group. The immobility time was significantly reduced by administration of standard drug, Moclobemide and JC-41 and JC-42, while more satisfactory results were obtained with compound JC-42 (**p<0.05) comparable to standard drug, Moclobemide (***p<0.001). Results are depicted in (figure 8).
Figure 8: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Tail Suspension test in a mouse model of depression induced by LPS. Values are presented as mean±SEM with a sample size of n = 6 per group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the LPS group.
c. Sucrose Preference Test:
Mice injected with LPS exhibited a significantly reduced desire for sucrose in comparison to mice that received saline treatment during the 0–24-hour period. These findings suggest that the concentration of LPS utilized in the current investigation falls within a suitable range for evaluating depressive-like behavior. Sucrose preference was increased in the treatment groups. Sugar preference was more in group 3 (standard drug, Moclobemide, ***p<0.001). Similar results were shown by group 5 (JC-42, **p<0.05). Results are depicted in (figure 9).
Figure 9: The impact of JC-41 and JC-42 therapy on motor skills was evaluated using the Sucrose preference test in a mouse model of depression produced by LPS. The values are presented as the mean ± standard error of the mean (SEM), with a sample size of 6 per group. Moclobemide demonstrated a highly significant activity (***p<0.001), while the JC-42 group showed a substantial activity (**p<0.05) compared to the LPS group.
d. Open field test:
Administering LPS led to a significant decrease in the number of line crossings in both the core and peripheral regions. Additionally, there was a decrease in the overall number of line crossings and the number of rears. Post hoc analysis revealed that administering Moclobemide and NCE (JC-42) before treatment effectively counteracted the decrease in the number of line crossings in both the center and periphery generated by LPS (***p<0.001 and **p<0.05, respectively), as well as the total number of line crossings. The treatment groups also reversed the decrease in the number of rears caused by LPS. The results are illustrated in (figure 10).
Figure 10: The impact of JC-41 and JC-42 therapy on motor functions was evaluated using an open field test in a mouse model of depression induced by LPS. The number of squares crossed (A) and the number of instances of rearing (B) were measured. The values are presented as the mean ± SEM, with a sample size of 6 per group. A statistically significant difference was observed in the Moclobemide group (***p<0.001) and JC-42 group (**p<0.05) compared to the LPS group.
Assessment of Biochemical Parameters:
a. Effect of JC-41 and JC-42 on GSH and Lipid peroxide level in LPS-induced depression:
The administration of LPS had a notable effect on levels of oxidative stress indicators, specifically MDA and GSH, in both cortex and hippocampus. Nevertheless, decrease in GSH levels and increase in MDA levels caused by LPS were counteracted by both usual medication treatment (50 mg/kg, ***p<0.001) and JC-42 (100 mg/kg, **p<0.05). Results have shown that JC-42 effectively reduced oxidative stress in mice produced by LPS. Results illustrated in (figure 11).
Figure 11: The impact of JC-41 and JC-42 therapy on biochemical markers, specifically the levels of reduced glutathione (GSH) (A) and malondialdehyde (MDA) (B), were evaluated in a depression model caused by lipopolysaccharide (LPS). The values are presented as the mean ± SEM, with a sample size of 6 per group. A statistically significant difference was observed in the Moclobemide group (***p<0.001) and JC-42 group (**p<0.05) compared to the LPS group.
DISCUSSION:
Depression is a highly prevalent and debilitating mental ailment that impacts a significant population worldwide, making it one of the most common psychiatric conditions. The symptoms of depression, such as experiencing profound sadness and a significant decrease in interest in activities, greatly impair an individual's functional capacity and general quality of life. In addition to its impact on mental health, depression is linked to other physical health issues, including cancer, diabetes, and cardiovascular disorders. Furthermore, it commonly coexists with serious central nervous system disorders such as Alzheimer's and Parkinson's disease, stroke, and chronic pain, which complicates its management. Although numerous categories of antidepressants have been created throughout the years, present therapies nonetheless possess notable restrictions. A multitude of often prescribed medications are accompanied by undesirable reactions that might be challenging for patients to endure, examples of adverse effects include cardiovascular, anticholinergic, neurologic, gastrointestinal, and several other consequences. The majority of synthetic antidepressants exert their effects on the biogenic amines in the brain, leading to an elevation in their levels within certain regions of the brain. MAO enzymes are essential for the deactivation of biogenic amines, making the inhibition of MAO a critical mode of action for antidepressants. Nevertheless, the MAO inhibitors now on the market frequently have significant adverse effects, including hypertension, tremors, muscle rigidity, and seizures. This underscores the necessity for more powerful antidepressants that have fewer or no side effects. This study examined the potential of two new chemical entities, JC-41 and JC-42, to function as antidepressants. These compounds were found to reduce the levels of the stress hormone corticosterone and suppress the generation of reactive oxygen species by selectively targeting MAO-A. Depressed patients often exhibit elevated levels of MAO-A in various regions of their brains. Both compounds had antidepressant properties in mice, with JC-42 exhibiting superior effectiveness compared to JC-41. Administration of corticosterone and LPS for a prolonged period in mouse models led to the development of symptoms of depression. These symptoms included a decreased preference for sucrose, elevated immobility was observed in assessments such as the FST and TST, together with decreased locomotor activity. The severity of depressive symptoms was reduced by administering JC-41 and JC-42, with JC-42 showing particularly promising results that are comparable to the established medicine Moclobemide. The compounds showed potential in regulating pathways associated with oxidative stress and reducing levels of serum corticosterone and MAO-A in the brain. This suggests an intricate mechanism of action in reducing depression. The findings underscore the promise of JC-41 and JC-42 as novel therapeutic strategies for depression, addressing both imbalances in neurotransmitters and oxidative stress. These findings warrant further investigation in clinical settings.
CONCLUSION:
Based on the findings of this study, the hit compounds JC-41 and JC-42 exhibited promising antidepressant properties that are similar to the widely prescribed antidepressant Moclobemide. The study demonstrated that both the compounds JC-41 and JC-42 efficiently alleviate the depression-like symptoms mimicking sadness by lowering the oxidative stress, as well as reducing the serum corticosterone and brain MAO-A levels. Compound JC-42 exhibited better antioxidant and corticosterone-restorative effects as compared to JC-41. Additionally, JC-42 may have an antidepressant impact via elevating the brain glutathione levels. However, further investigations are required to ascertain the exact role of neurotransmitters and other pathways involved in the antidepressant activity of these compounds. These additional mechanistic studies are required to elucidate these findings, and could potentially aid in the development of new therapeutic strategy for the treatment of depression.
CONFLICT OF INTEREST:
The authors declare no conflict of interests.
ACKNOWLEDGMENTS:
The authors express their gratitude to Amity University for their generous assistance during the project.
REFERENCES:
1. Benazzi F. Various forms of depression. Dialogues in Clinical Neuroscience. 2006; 8(2): 151-61.
2. Grover S. Dutt A. An overview of Indian research in depression. Indian J Psychiatry. 2010; 52(7): 178-188.
3. Kessler RC. Bromet EJ. The epidemiology of depression across cultures. Annual Review of Public Health. 2013; 34: 119–38.
4. Anastasiou E. Lorentz KO. Stein GJ. Mitchell PD. Prehistoric schistosomiasis parasite found in the Middle East. The Lancet Infectious Diseases. Lancet Publishing Group; 2014; 14: 553–4.
5. Gourley SL. Wu FJ. Taylor JR. Corticosterone regulates pERK1/2 map kinase in a chronic depression model. In: Annals of the New York Academy of Sciences. Blackwell Publishing Inc. 2008: 509–14.
6. Johnson SA. Fournier NM. Kalynchuk LE. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behavioural Brain Research. 2006; 168(2): 280–8.
7. Weng L. Guo X. Li Y. Yang X. Han Y. Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice. Eur J Pharmacol. 2016; 774: 50–4.
8. Zhuo R, Cheng X, Luo L, Yang L, Zhao Y, Zhou Y, Peng L, Jin X, Cui L, Liu F, Yang L. Cinnamic acid improved lipopolysaccharide-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in mice. Pharmacology. 2022; 107(5-6): 281-9.
9. Ren J. Fan C. Chen N. Huang J. Yang Q. Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in Rats. Neurochem Res. 2011; 36(12): 2352–62.
10. Bielecka AM. Paul-Samojedny M. Moclobemide exerts an anti-inflammatory effect in lipopolysaccharide-activated primary mixed glial cell culture. Naunyn Schmiedebergs Arch Pharmacol. 2010; 382(5–6): 409–17.
11. Indu Sharma, Mandeep Kaur, Bharat Parashar, Amrita Kainth. Depression: An Overview. Asian J. Res. Pharm. Sci. 2014; 4(1): 28-31.
12. Manpreet Kaur, Sukhpreet Kaur, Rajwant Kaur. Correlation of Depression and Quality of life among rural elderly. Int. J. Adv. Nur. Management. 2016; 4(4): 323-326.
13. Sakshi Bhardwaj, Sonal Dubey. Qsar and Docking Studies of Some Novel Piperine Analogues as Monoamine Oxidase Inhibitors. Asian Journal of Research in Pharmaceutical Sciences. 2022; 12(2): 115-2.
14. Mcewen BS. Allostasis. Allostatic Load. and the Aging Nervous System: Role of Excitatory Amino Acids and Excitotoxicity. Neurochemical Research. 2000; 25(9-10): 1219-31.
15. Popoli M. Yan Z. McEwen BS. Sanacora G. The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission. Nature Reviews Neuroscience. 2012; 13: 22–37.
16. Liston C. Miller MM. Goldwater DS. Radley JJ. Rocher AB. Hof PR. et al Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. Journal of Neuroscience. 2006; 26(30): 7870–4.
17. Klein DF. Endogenomorphic Depression A Conceptual and Terminological Revision. 1973.
18. Planchez B. Surget A. Belzung C. Animal models of major depression: drawbacks and challenges. Journal of Neural Transmission. Springer-Verlag Wien.2019; 126(11): 1383-1408.
19. G. Venkatesha, C. Kalaiyarasia, M. Ramanathana. Antidepressant like Effect of Gabapentin Decreases the Immobility Time in Despair Animal Models in Mice: Roll of Serotonergic System in it. Research J. Pharm. and Tech. Nov. 2011; 4(11): 1702-1706.
20. Bansal S, Dhingra. Behavioral, Biochemical and Histopathological Evaluation of Sinapic acid for Antidepressant activity in normal mice and stressed mice. Research Journal of Pharmacy and Technology 2023; 16(8):3569-7.
21. Sachin Neekhra, Himani Awasthi, Dharmchand Prasad Singh. Streblus asper attenuates stress-induced physical and Biochemical changes in Rat Model. Research Journal of Pharmacy and Technology. 2021; 14(4): 1910-4.
22. Juna Thomas, Veeresh Babu. D, Anjan Kumar, Narayana Swamy V B. Studies on Anti-Depressant Activity of Perment-A Polyherbal Formulation in Experimental Animal Models. Research J. Pharmacology & Pharmacodynamics. 2016; 8(2): 45-54.
23. Bai Y. Song L. Dai G. Xu M. Zhu L. Zhang W. et al. Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection. Steroids. 2018; 135: 73–8.
24. Anantha Lakshmi J, Satyavthi D. Evaluation of Anti-Depressant and MAO Inhibitory Activity of Rhodiola rhodantha rhizome methanolic extract. Research J. Pharm. and Tech. 2015; 8(3): 310-315.
25. Uchiyama M. Mihara M. Determination of Malonaldehyde Precursor in Tissues by Thiobarbituric Acid Test. Analytical Biochemistry. 1978; 86(1): 271-8.
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Received on 30.07.2024 Revised on 16.12.2024 Accepted on 15.02.2025 Published on 01.07.2025 Available online from July 05, 2025 Research J. Pharmacy and Technology. 2025;18(7):3314-3323. DOI: 10.52711/0974-360X.2025.00479 © RJPT All right reserved
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