Administration Of Amitriptyline Research Articles

Amitriptyline and cholecalciferol amend hippocampal histological structure and myelination during stress in Wistar rats via regulating miR200/BMP4/Olig-2 signaling.

Chronic stress is a universal condition commonly associated with many psychiatric diseases. An extensive body of evidence discussed hippocampal affection upon chronic stress exposure, however, the underlying molecular pathways still need to be identified. We investigated the impact of chronic stress on miR200/BMP/Olig-2 signaling and hippocampal myelination. We also compared the effects of chronic administration of amitriptyline and cholecalciferol on chronically stressed hippocampi. Both amitriptyline and cholecalciferol significantly decreased serum cortisol levels, reduced immobility time in the forced swim test, increased the number of crossed squares in open field test, decreased the hippocampal expression of bone morphogenetic protein 4 (BMP4) and its messenger RNA (mRNA) levels, reduced miR200 expression as compared to untreated chronically stressed rats. Also, both drugs amended the hippocampal neuronal damage, enhanced the surviving cell count, and increased the pyramidal layer thickness of Cornu Ammonis subregion 1 (CA1) and granule cell layer of the dentate gyrus. Cholecalciferol was more effective in increasing the area percentage of myelin basic protein (MBP) and Olig-2 positive cells count in hippocampi of chronic stress-exposed rats than amitriptyline, thus enhancing myelination. We also found a negative correlation between the expression of BMP4, its mRNA, miR200, and the immunoexpression of MBP and Olig-2 proteins. This work underscores the amelioration of the stress-induced behavioral changes, inhibition of miR200/BMP4 signaling, and enhancement of hippocampal myelination following chronic administration of either amitriptyline or cholecalciferol, though cholecalciferol seemed more effective in brain remyelination.

ИЗМЕНЕНИЯ САРКОЛЕММАЛЬНОГО КАВЕОЛИНА-3 КАК РЕЗУЛЬТАТ ЦЕРАМИД-АССОЦИИРОВАННЫХ ЭФФЕКТОВ КИСЛОЙ СФИНГОМИЕЛИНАЗЫ ПРИ 14-ДНЕВНОЙ ФУНКЦИОНАЛЬНОЙ РАЗГРУЗКЕ КАМБАЛОВИДНОЙ МЫШЦЫ КРЫС

It is well known that functional unloading leads to a number of complex changes in the lipid-protein structural components in the sarcolemmal compartment of postural muscles' fibers. Among these changes are an increase of the sarcolemmal ceramide content, loss in cholesterol density in the lipid rafts fraction, a decrease of membrane sphingomyelin as a result of acid sphingomyelinase (ASM) activation and enhanced hydrolysis of sphingomyelin. These changes may underlie damages and primary elimination of damaged parts of muscle fibers' plasma membrane. Secondary reparation of sarcolemma depends on reorganization of the subsarcolemmal cytoskeleton. It appears to be exocytosis of caveolin-enriched vesicles in response to the growth of ASM dependent hydrolysis in the plasma membrane of muscle fibers. In our study, immunofluorescence microscopy and Western blot analysis were used to investigate ceramide and caveolin-3 changes in the sarcolemmal compartment of muscle fibers and total m. soleus from rats subjected to 14-d hindlimb unloading or unloading with administration of ASM inhibitor amitriptyline. In addition, muscle preparations with added exogenous sphingomyelinase were subjected to ex vivo analysis of ceramide and caveolin-3 immunofluorescence. The 14-d unloading led to the growth of ceramide and caveolin-3 immunofluorescence on muscle sections. Ex vivo analysis also demonstrated a significant increase of ceramide and caveolin-3 content in muscle fibers exposed to exogenous sphingomyelinase. The increase of caveolin-3 sarcolemmal density was confirmed by Western blot assay which indicated the growth of its amount in isolated sarcolemmal fraction. These changes were not observed in total homogenates of the unloaded m. soleus. Thus, functional unloading of the postural muscle leads to the accumulation of ceramide in the plasma membrane of muscle fibers and an increase in the level of membrane caveolin-3.

Oral proniosomal amitriptyline and liraglutide for management of diabetic neuropathy: Exceptional control over hyperglycemia and neuropathic pain

Exploitation of nanocarriers provides a compartment for enclosing drugs to protect them from degradation and potentiate their therapeutic efficiency. In the current study, amitriptyline- and liraglutide-loaded proniosomes were constructed for management of diabetic neuropathy, a serious complication associated with diabetes, that triggers spontaneous pain in patients and results in impaired quality of life. The developed therapeutic proniosomes were extensively characterized via dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and Fourier transform-infrared spectroscopy. High entrapment efficiency could be attained for both drugs in the proniosomes, and the reconstituted amitriptyline- and liraglutide-loaded niosomes possessed spherical morphology and particle sizes of 585.3 nm and 864.4 nm, respectively. In a diabetic neuropathy rat model, oral administration of the developed amitriptyline- and liraglutide-loaded proniosomes significantly controlled blood glucose levels, reduced neuropathic pain, oxidative stress and inflammatory markers, and improved histological structure of the sciatic nerve as compared to the oral and subcutaneous administration of amitriptyline and liraglutide, respectively. Loading of the tricyclic antidepressant amitriptyline and the antidiabetic peptide liraglutide into proniosomes resulted in exceptional control over hyperglycemia and neuropathic pain, and thus could provide an auspicious delivery system for management of neuropathic pain and control of blood glucose levels.

Amitriptyline efficacy in decreasing implant-induced foreign body reaction.

Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant-induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin-1β (IL-1β) or fibrogenic parameters (collagen, TGF-β, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7-day-old implants. However, AM was able to downregulate angiogenesis and FBR in 14-day-old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices.

Duloxetine and Amitriptyline Reduce Neuropathic Pain by Inhibiting Primary Sensory Input to Spinal Dorsal Horn Neurons via α1- and α2-Adrenergic Receptors.

Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin transporters at presynaptic terminals raises extracellular concentrations of norepinephrine. The α1- and α2-adrenergic receptor agonists inhibit glutamatergic input from primary afferent nerves to the spinal dorsal horn. However, the contribution of spinal α1- and α2-adrenergic receptors to the analgesic effect of antidepressants and associated synaptic plasticity remains uncertain. In this study, we showed that systemic administration of duloxetine or amitriptyline acutely reduced tactile allodynia and mechanical and thermal hyperalgesia caused by spinal nerve ligation in rats. In contrast, duloxetine or amitriptyline had no effect on nociception in sham rats. Blocking α1-adrenergic receptors with WB-4101 or α2-adrenergic receptors with yohimbine at the spinal level diminished the analgesic effect of systemically administered duloxetine and amitriptyline. Furthermore, intrathecal injection of duloxetine or amitriptyline similarly attenuated pain hypersensitivity in nerve-injured rats; the analgesic effect was abolished by intrathecal pretreatment with both WB-4101 and yohimbine. In addition, whole-cell patch-clamp recordings in spinal cord slices showed that duloxetine or amitriptyline rapidly inhibited dorsal root-evoked excitatory postsynaptic currents in dorsal horn neurons in nerve-injured rats but had no such effect in sham rats. The inhibitory effect of duloxetine and amitriptyline was abolished by the WB-4101 and yohimbine combination. Therefore, antidepressants attenuate neuropathic pain predominantly by inhibiting primary afferent input to the spinal cord via activating both α1- and α2-adrenergic receptors. This information helps the design of new strategies to improve the treatment of neuropathic pain.

Role of Oral Supplementation of Damiana (Turnera diffusa) Reduces the Renal Toxicity, Apoptosis and DNA Damage Associated with Amitriptyline Administration in Rats

Major depressive disorder and anxiety disorders are two mental diseases that are treated with amitriptyline (AMT). AMT treatments induced liver, heart and testes toxicity; As a result, the purpose of this study was to determine the preventative and therapeutic role of damiana (Dam) as adjuvant herbal therapy against AMT induced heart injury in rats. Six groups of 36 rats (male albino) were randomly assigned; first one is control, second is Dam, third was AMT, fourth was Dam+AMT, fifth was AMT+Dam and sixth was AMT self-healing. A significant elevation in creatinine, urea, sodium (Na+), Chloride (Cl+), renal injury, DNA damage and apoptosis in treatment rats with amitriptyline and self-healing group as related to control and damiana groups. Conversely; potassium (K+) and calcium (Ca++) were a significant decrease in AMT and self-healing groups as compared with control. Treatment of AMT with Dam (Co and Post) revealed a modulation and improvement of renal toxicity with best result in co- treatments than post treatments. As a result, AMT treatments encouraged changes in kidney functions and structure and the post-treatments of AMT with dam modulates these alterations.

Histological, immunohistochemical and radiographic evaluation of Amitriptyline administration on the periodontium of albino rats (An experimental study)

BackgroundAmitriptyline is a tricyclic antidepressant drug accustomed to treat depressive disorders. It recorded many side effects on different tissues. ObjectiveTo investigate reaction of Albino rats’ periodontium after oral administration of Amitriptyline histologically and radiographically. MethodsFourteen adult male albino rats (150–200 g) were divided into two groups, control and experimental. Rats of experimental group received 10 mg⁄kg⁄day of Amitriptyline hydrochloride by oral gavage for four weeks. Mandibles were prepared for hematoxylin and eosin (H&E) and anti-osteopontin (Anti-OPN) immunohistochemistry staining. Bone mineral density was measured in mandibular alveolar bone. Statistical analysis for Anti-OPN and relative Hounsfield unit value (HU value) was performed using independent-samples t-test. ResultsGingiva of experimental group showed epithelial degeneration with pyknotic nuclei and disintegration in lamina propria. Areas of separation in alveolar bone and degeneration of some regions in cementum were seen with apparent increase in periodontal ligament (PDL) thickness and its detachment from bone and cementum at some regions. Immunohistochemical examination of experimental group showed apparently increased immunopositivity in gingiva, cementocytes, osteocytes, cementum, bone matrices, fibroblasts and PDL fibers when compared to control group. Statistical analysis revealed insignificant difference of Anti-OPN area% in gingiva between both studied groups. While there was statistical significant increase of Anti-OPN area% in the other periodontium tissues and high statistical significant decrease of relative HU value in experimental group when compared to control. ConclusionsAmitriptyline has destructive effect on periodontal tissues and statistically increases the expression of Anti-OPN in all periodontal tissues except gingiva and decreases bone mineral density.

Crosstalk between epithelial sodium channels (ENaC) and basolateral potassium channels (Kir 4.1/Kir 5.1) in the cortical collecting duct.

Inwardly rectifying K+ (Kir ) channels located on the basolateral membrane of epithelial cells of the distal nephron play a crucial role in K+ handling and BP control, making these channels an attractive target for the treatment of hypertension. The purpose of the present study was to determine how the inhibition of basolateral Kir 4.1/Kir 5.1 heteromeric K+ channel affects epithelial sodium channel (ENaC)-mediated Na+ transport in the principal cells of cortical collecting duct (CCD). The effect of fluoxetine, amitriptyline and recently developed Kir inhibitor, VU0134992, on the activity of Kir 4.1, Kir 4.1/Kir 5.1 and ENaC were tested using electrophysiological approaches in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCDcl1 cells and freshly isolated rat and human CCD tubules. To test the effect of pharmacological Kir 4.1/Kir 5.1 inhibition on electrolyte homeostasis in vivo and corresponding changes in distal tubule transport, Dahl salt-sensitive rats were injected with amitriptyline (15 mg·kg-1 ·day-1 ) for 3 days. We found that inhibition of Kir 4.1/Kir 5.1, but not the Kir 4.1 channel, depolarizes the cell membrane, induces the elevation of intracellular Ca2+ concentration and suppresses ENaC activity. Furthermore, we demonstrate that amitriptyline administration leads to a significant drop in plasma K+ level, triggering sodium excretion and diuresis. The present data uncover a specific role of the Kir 4.1/Kir 5.1 channel in the modulation of ENaC activity and emphasize the potential for using Kir 4.1/Kir 5.1 inhibitors to regulate electrolyte homeostasis and BP.

Effect of Systemic Administration of Amitriptyline on Oral Microbes in Rats.

Amitriptyline is a major tricyclic antidepressant that is also used to relieve chronic orofacial pain. Recently, alterations in gut flora due to various antidepressants have been demonstrated. However, it remains unknown how antidepressants affect the oral environment, including microbiota and innate immunity. The aim of this study was to investigate the effects of amitriptyline on oral microflora and antimicrobial peptides. Sprague-Dawley rats were intraperitoneally injected with amitriptyline for 2 weeks. The DNA extracted from the oral swabs were used to perform 16SrRNA sequencing to evaluate the oral microbiome. Quantitative RT-PCR was performed to evaluate the mRNA levels of antimicrobial peptides in the buccal tissues. No significant differences in salivary flow rates were observed between the amitriptyline and control groups. Taxonomic analysis showed significant alterations in bacteria such as Corynebacterium, Rothia, and Porphyromonas due to amitriptyline administration. The beta diversity showed significant differences between the amitriptyline and control groups. Additionally, the predicted metagenome functions were significantly different between the two groups. The mRNA expression levels of antimicrobial peptides in the amitriptyline group were significantly higher as compared to controls. Systemic administration of amitriptyline may affect the oral environment, including oral microbes and innate immunity in the oral mucosa.

Postinjury treatments to make early tactical aeromedical evacuation practical for the brain after TBI.

Traumatic brain injury (TBI) is common in civilians and military personnel. No potential therapeutics have been evaluated to prevent secondary injury induced by the hypobaric hypoxia (HH) environment integral to postinjury aeromedical evacuation (AE). We examined the role of allopurinol, propranolol, adenosine/lidocaine/magnesium (ALM), or amitriptyline administration prior to simulated flight following murine TBI. Mice underwent TBI and were given allopurinol, propranolol, amitriptyline, or ALM prior to simulated AE or normobaric normoxia (NN) control. Heart rate (HR), respiratory rate, and oxygen saturation (Spo2) were recorded throughout simulated AE. Mice were sacrificed at 24 hours, 7 days, or 30 days. Serum and cerebral cytokines were assessed by enzyme-linked immunosorbent assay. Motor function testing was performed with Rotarod ambulation. Immunohistochemistry was conducted to examine phosphorylated tau (p-tau) accumulation in the hippocampus at 30 days. While all treatments improved oxygen saturation, propranolol, amitriptyline, and allopurinol improved AE-induced tachycardia. At 24 hours, both propranolol and amitriptyline reduced tumor necrosis factor alpha levels while allopurinol and ALM reduced tumor necrosis factor alpha levels only in NN mice. Propranolol, amitriptyline, and ALM demonstrated lower serum monocyte chemoattractant protein-1 7 days after AE. Both amitriptyline and allopurinol improved Rotarod times for AE mice while only allopurinol improved Rotarod times for NN mice. Propranolol was able to reduce p-tau accumulation under both HH and NN conditions while ALM only reduced p-tau in hypobaric hypoxic conditions. Propranolol lowered post-TBI HR with reduced proinflammatory effects, including p-tau reduction. Amitriptyline-induced lower post-TBI HR and improved functional outcomes without affecting inflammatory response. Allopurinol did not affect vital signs but improved late post-TBI systemic inflammation and functional outcomes. Adenosine/lidocaine/magnesium provided no short-term improvements but reduced p-tau accumulation at 30 days in the HH cohort. Allopurinol may be the best of the four treatments to help prevent short-term functional deficits while propranolol may address long-term effects. Basic science article.

Decreased connexin43 expression in the hippocampus is related to the antidepressant effect of amitriptyline in neuropathic pain mice

Downregulation of astrocytic connexin43 (Cx43) has been observed in several brain regions in rodents and patients with depression. However, its specific role in this effect remains unknown. Moreover, chronic pain can induce depressive disorders. Therefore, the current study examined the relationship between Cx43 expression and depressive-like behavior in a neuropathic pain model. Neuropathic pain was induced by spared nerve injury (SNI) in mice. Depressive-like behavior was evaluated using the forced swim test. Expression of Cx43 in the hippocampus was evaluated using Western blotting and real-time PCR. SNI downregulated Cx43 protein in the contralateral hippocampus of mice, whereas expression of hippocampal Cx43 mRNA was not altered following SNI. Although SNI mice showed longer immobility time compared with sham mice during the forced swim test, duration of depressive-like behavior was not correlated with the expression of Cx43 in the hippocampus of SNI mice. Repeated intraperitoneal administration of amitriptyline ameliorated SNI-induced depressive-like behavior. Furthermore, the antidepressant effect of amitriptyline was correlated with decreased hippocampal Cx43 expression in SNI mice. The current findings suggest that the alteration of Cx43 expression in the hippocampus may not be involved in the induction of depressive disorder but may influence the efficacy of antidepressants. Therefore, the level of Cx43 expression in the hippocampus could be a key parameter to evaluate individual differences in antidepressant effects in patients with depressive disorder.

Role of Basolateral K ir 4.1/K ir 5.1 Channel in the Regulation of Electrolyte Balance and ENaC Activity in the Cortical Collecting Duct

Recent genetic studies identified a critical role of basolateral inwardly rectifying K+ (Kir) channels of the distal nephron in K+ homeostasis and blood pressure control, making these channels attractive targets for hypertension treatment. The main aim of the present study was to examine the effect of established and newly discovered inhibitors of basolateral Kir channels amitriptyline, fluoxetine, and VU0134992 on the epithelial sodium channel (ENaC) activity in the cortical collecting duct (CCD). We show that inhibition of heteromeric Kir4.1/Kir5.1, but not homomeric Kir4.1 channel, substantially suppressed both amiloride-sensitive equivalent short-circuit current in cultured polarized epithelial mCCDcl1 cells and single-channel ENaC activity in principal cells of rat and human CCD tubules. Using the combination of confocal microscopy, FluoVolt™ voltage-sensitive dye, and Fluo8HT Ca2+ dye, we show that acute application of amitriptyline or VU992 in concentrations that produce an inhibitory effect on Kir4.1/Kir5.1 channel resulted in substantial depolarization of cellular membrane potential and increase in intracellular Ca2+ level in mCCDcl1 cells that can explain a significant decrease of ENaC open probability without altering channel conductance induced by these drugs. Furthermore, we evaluated the effect of nonspecific Kir inhibitor amitriptyline on electrolyte homeostasis and apical Na+ transporters' expression in the distal nephron in Dahl salt-sensitive (SS) rats. The administration of amitriptyline for three days led to a significant drop in plasma K+, an increase in Na+ and K+ excretion, and diuresis. These changes were accompanied by the compensatory overexpression of ENaC and total and phosphorylated forms of thiazide-sensitive Na+-Cl-- cotransporter. Our data uncovered the putative mechanism of the impact of basolateral Kir4.1/Kir5.1 channel inhibition on ENaC activity and further emphasized a specific role of this channel in regulation of blood K+ level and electrolyte homeostasis.

The Effect of Amitriptyline and Sertraline on the Tooth Movement, Root Resorption and Alveolar Bone Remodeling After Load Application in Dogs

Introduction: Antidepressant drugs are the most commonly prescribed classes of pharmacologic agents in the public. The drugs have been shown to have a role in the regulation of bone cell function and as a result affecting the orthodontic tooth movements. The aim of this study was to determine the effect of Amitriptyline and Sertraline on the tooth movement, root resorption and alveolar bone remodeling after load application in dogs. Materials and Methods: In this experimental study, 9 male dogs were randomly divided into three groups, first group sertraline, second group Amitriptyline and the control group (normal saline). A nickel titanium spring (200 gr) was used between second premolar and canine after 1st premolar extraction. After 2 months, the reduction of distance between 2nd premolar and canine was measured. The percentages of root resorption and bone formation were determined. The data were analyzed using repeated measures analysis at significance level of 0.05. Results: In the three groups of amitriptyline, sertraline and control, the mean of teeth movement (p value = 0.483), external root resorption (p value = 0.608), total bone mineral density (p value = 0.078), bone formation percentage (p value = 0.616) and immature and lamellar bone formation (p value = 0.083), there was no statistical difference in any group and in premolar teeth Conclusions: The rate of tooth movement and the percentages of bone formation and root resorption in dogs decreased with systemic administration of amitriptyline and sertraline; although this reduction was not statistically significant in comparison with control group.

Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress

Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota–gut–brain axis. But the impact of antidepressants on gut microbiota function and composition remains poorly understood. Thus this study assessed the effect of serotonin reuptake inhibitor antidepressant fluoxetine (Flu) and tricyclic antidepressant amitriptyline (Ami) administration on gut microbiota composition, diversity, and species abundance, along with microbial function in a chronic unpredictable mild stress (CUMS)-induced depression rat model. Oral administration of Ami and Flu significantly altered the overall gut microbiota profile of CUMS-induced rats, as assessed using the permutational multivariate analysis of variance test. At the phylum level, 6-week of antidepressant treatment led to a decreased Firmicutes/Bacteroidetes ratio due to an enhanced Bacteroidetes and reduced Firmicutes relative abundance. Flu was more potent than Ami at altering the Firmicutes and Bacteroidetes levels in the CUMS rats. At the family level, both antidepressants significantly increased the abundance of Porphyromonadaceae. However, an increased Bacteroidaceae level was significantly associated with Ami, not Flu treatment. Furthermore, at the genus level, an increase in the relative abundance of Parabacteroides, Butyricimonas, and Alistipes was observed following Ami and Flu treatment. Subsequent metagenomics and bioinformatics analysis further indicated that Ami and Flu likely also modulated metabolic pathways, such as those involved in carbohydrate metabolism, membrane transport, and signal transduction. Additionally, both antidepressants affected antibiotic resistome, such as for aminoglycoside (aph3iiiA), multidrug (mdtK, mdtP, mdtH, mdtG, acrA), and tetracycline (tetM) resistance in CUMS rats. These data clearly illustrated the direct impact of oral administration of Flu and Ami on the gut microbiome, thus set up the foundation to reveal more insights on the therapeutic function of the antidepressants and their overall contribution to host health.

経管栄養患者に対する三環系抗うつ薬投与による唾液分泌抑制効果の検討

In patients being fed with a nasogastric tube (NGT) or gastrostomy tube, over secretion of saliva can cause aspiration pneumonia. Tricyclic antidepressants (TCA), which has an anti-cholinergic effect, is used at our hospital for patients with hypersalivation. The efficacy and safety in the suppression of saliva secretion with the use of tricyclic antidepressants, such as amitriptyline (AMT), were examined. From January 2018 to May 2019, patients who had hypersalivation, were suffering from aspiration pneumonia and who were supported by the nutrition support team (NST), were administered AMT. Comparison of the frequency of saliva suctioning and the course of disease, before and after AMT use, was carried out in 6 patients. A significant decrease in the frequency of suctioning was observed in all 6 patients after 1 week of AMT administration. Four patients had NGT and 3 of them were able to have gastrostomy with continuous AMT use. Four patients were discharged from the hospital to their home or a nursing home. Aspiration pneumonia occurred in only 1 patient and AMT dosage was decreased in 1 patient due to dry mouth. Medical accidents, such as self-removal of NGT or IV tubing, due to delirium caused by antidepressants are of deep concern. Initial and continuous use of TCA must be taken into careful consideration. Adverse reactions to TCA are relatively mild in most cases. Early detection and treatment and evaluation of the balance between a patient’s physical burden and the effectiveness of inhibiting saliva secretion are very important.

Therapeutic Effects of Turnera diffusa Extract Against Amitriptyline-Induced Toxic Hepatic Inflammation

Tricyclic Antidepressants Including Amitriptyline (AMI), stop the reabsorption of norepinephrine and serotonin, so the levels of transmitters is elevated in the brain to lead to several side effects. Therefore, current study aimed to assay liver dysfunction that attended by AMI administration and monitoring of damiana Turnera diffuse role as adjuvant therapy to improving amitriptyline hepatic effects in male rats. 60 rats (adult, male, albino) were used divided into six groups (n = 10); 1st group, control; 2nd group, damiana; 3rd group, AMI; 4th group, co-treated AMI with damiana; 5th group, post-treated AMI with damiana and 6th group, self-healing AMI. Results showed that; AMI induces an elevation in AST, ALT and ALP; while it reduced albumin and total protein content. Besides, autoimmune liver disorders (ANA), hepatic DNA damage, p53 and PCNA protein expressions and histopathological injury were detected. However, the groups administered with damiana showed positive effects by increasing cellular response and reducing pathological changes. It concluded that treatment with AMI causes liver dysfunction, while damiana can: Protective against the toxic effects induced by AMI in rats.

Anti-inflammatory effect of amitriptyline in a rat model of acetic acid-induced colitis: the involvement of the TLR4/NF-kB signaling pathway.

Inflammatory bowel disease (IBD) consists of ulcerative colitis and Crohn's disease, which affects gastrointestinal tract. The immune-mediated inflammation is mostly considered as the pathogenesis of IBD. It has been demonstrated that amitriptyline exerts anti-inflammatory influence; therefore, the aim of the current experiment is to evaluate the anti-inflammatory impact of amitriptyline on intestinal disorders following acetic acid-induced colitis in rats. Thirty male Wistar rats were randomly divided into five groups, including sham, control, dexamethasone (2mg/kg), and amitriptyline (10 and 20mg/kg). Intrarectal administration of acetic acid was applied to colitis induction in all study groups except for sham group. Animals were treated by oral administration of dexamethasone or amitriptyline. While macroscopic and microscopic lesions appeared after colitis induction treatment with dexamethasone and amitriptyline 10 and 20mg/kg significantly improved lesions. Moreover, Toll-like receptor 4 (TLR4) and nuclear factor binding kappa light-chain (NF-ĸB expression), tumor necrosis factor-alpha (TNF-α) level, and myeloperoxidase (MPO) activity were increased after colitis induction, whereas treatment with dexamethasone (2mg/kg) or amitriptyline (10 and 20mg/kg) caused a noticeable decrease in the TLR4 and pNF-ĸB expression, TNF-α level, and MPO activity. In conclusion, amitriptyline plays an anti-inflammatory role through the suppression of TLR4/pNF-ĸB signaling pathway in the rat model of acute colitis.

Analysis of the effects of a tricyclic antidepressant on secondary sleep disturbance induced by chronic pain in a preclinical model

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Effect of Single and Repeated Administration of Amitriptyline on Experimental Gastric Ulcer

Amitriptyline is an antidepressant drug widely used as analgesic in the management of chronic pain syndromes. It is also attracting the attention of researchers as an alternative agent for peptic ulcer management because studies have shown that most patients with peptic ulcer also suffer from depression. Thus, this study was conducted to investigate gastroprotective effects of single and repeated dose administration of amitriptyline against indomethacin-induced gastric injury in rats. Rats were randomly divided into three groups of eight rats/each. For 14 days, Group I (control) and Group II (single dose) received distilled water; Group III (repeated dose) received 10 mg/kg amitriptyline orally once daily. On day 15, Group I was given distilled water; Group II and III were given 10 mg/kg amitriptyline orally. Thirty minutes later, indomethacin (25 mg/kg) was administrated orally to all the groups. Six hours after indomethacin administration, animals were sacrificed under thiopental sodium anaesthesia, stomachs were rapidly removed, cut along the greater curvature and cleaned. The stomachs were macroscopically evaluated; total area of stomach and visible ulcerated areas were measured using millimeter square paper. Finally, the stomachs were fixed in 10% formalin for histopathologic valuation. Single dose administration of amitriptyline significantly reduced ulcer indexes and gastric erosions as compared to the control group.However, its role against inflammatory reactions such as necrosis, polymorphonuclear leucocyte infiltration, neutrophil and eosinophil reactions were statistically insignificant. On the other hand, repeated dose administration of amitriptilyine produced significant gastroprotective effects as observed from macroscopical and histopathological evaluation results. Moreover, there was also a significant difference in the gastroprotective effects between single and repeated dose of amitriptyline against indomethacin-induced gastric damage. In conclusion, the results of this study evealed that repeated dose administration of amitriptyline showed better gastroprotective effects compared to single dose amitriptyline administration and the control group.
 Keywords: amitriptyline, gastroprotective effects, indomethacin, histopathologic evaluation, rats

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear.

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM−/−) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM−/− mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM−/− mice, while the same treatment reduced social fear in ASM+/− mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM−/− mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM−/− mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments.