Primidone inhibits TRPM3 and attenuates thermal nociception in vivo.

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 µM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice.

BACKGROUND: Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing µ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice. METHODS: Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus. RESULTS: Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p < 0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive. CONCLUSIONS: Overall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain.

Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida.

Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

Effect of glibenclamide on antinociceptive effects of antidepressants of different classes.

OBJECTIVES: The purpose of this work was to determine whether the intraperitoneal administration of glibenclamide as a K ATP channel blocker could have an effect on the antinociceptive effects of antidepressants with different mechanisms of action. METHODS: Three antidepressant drugs, amitriptyline as a dual-action, nonselective inhibitor of noradrenaline and a serotonin reuptake inhibitor, fluvoxamine as a selective serotonin reuptake inhibitor and maprotiline as a selective noradrenaline reuptake inhibitor, were selected, and the effect of glibenclamide on their antinociceptive activities was assessed in male Swiss mice (25-30 g) using a formalin test. DISCUSSION: None of the drugs affected acute nociceptive responses during the first phase. Amitriptyline (5, 10 mg/ kg), maprotiline (10, 20 mg/kg) and fluvoxamine (20 and 30 mg/kg) effectively inhibited pain induction caused by the second phase of the formalin test. Glibenclamide (5 mg/kg) alone did not alter licking behaviors based on a comparison with the control group. However, the pretreatment of animals with glibenclamide (10 and 15 mg/kg) partially reversed the antinociceptive effects of fluvoxamine but not those of maprotiline. In addition, the highest dose of glibenclamide (15 mg/kg) partially prevented the analgesic effect of amitriptyline. CONCLUSION: Therefore, it seems that adenosine triphosphate-dependent potassium channels have a major role in the analgesic activity of amitriptyline and fluvoxamine.

Effect of glibenclamide on antinociceptive effects of antidepressants of different classes

OBJECTIVES: The purpose of this work was to determine whether the intraperitoneal administration of glibenclamide as a K ATP channel blocker could have an effect on the antinociceptive effects of antidepressants with different mechanisms of action. METHODS: Three antidepressant drugs, amitriptyline as a dual-action, nonselective inhibitor of noradrenaline and a serotonin reuptake inhibitor, fluvoxamine as a selective serotonin reuptake inhibitor and maprotiline as a selective noradrenaline reuptake inhibitor, were selected, and the effect of glibenclamide on their antinociceptive activities was assessed in male Swiss mice (25-30 g) using a formalin test. DISCUSSION: None of the drugs affected acute nociceptive responses during the first phase. Amitriptyline (5, 10 mg/ kg), maprotiline (10, 20 mg/kg) and fluvoxamine (20 and 30 mg/kg) effectively inhibited pain induction caused by the second phase of the formalin test. Glibenclamide (5 mg/kg) alone did not alter licking behaviors based on a comparison with the control group. However, the pretreatment of animals with glibenclamide (10 and 15 mg/kg) partially reversed the antinociceptive effects of fluvoxamine but not those of maprotiline. In addition, the highest dose of glibenclamide (15 mg/kg) partially prevented the analgesic effect of amitriptyline. CONCLUSION: Therefore, it seems that adenosine triphosphate-dependent potassium channels have a major role in the analgesic activity of amitriptyline and fluvoxamine.

Effects of repeated maprotiline and fluoxetine treatment on gene expression of catecholamine synthesizing enzymes in adrenal medulla of unstressed and stressed rats.

1 Repeated maprotiline (a noradrenaline reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor) treatment on gene expression of catecholamine biosynthetic enzymes were examined in adrenal medulla of unstressed control and chronic unpredictable mild stressed rats. 2 Maprotiline did not change gene expression of catecholamine biosynthetic enzymes in control and stressed rats. 3 Fluoxetine increased gene expression of tyrosine hydroxylase (TH) and dopamine-ß-hydroxylase (DBH), but did not phenylethanolamine N-methyltransferase in both unstressed and chronic unpredictable mild stressed animals. 4 In conclusion, we have demonstrated that repeated administration of fluoxetine enhanced gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in adrenal medulla of control and stressed rats.

Central and peripheral anti-inflammatory effects of maprotiline on carrageenan-induced paw edema in rats.

OBJECTIVE: To explore the site of action of maprotiline, as an atypical antidepressant, on carrageenan-induced paw edema. SUBJECTS: Male Wistar rats were used. METHODS: Firstly, the anti-inflammatory effect of systemic maprotiline (12.5, 25 and 50 mg kg(-1)) was assessed using a paw edema model. Secondly, different doses of maprotiline were administrated intracerebroventricularly, intrathecally and locally before carrageenan challenge. Finally, we tried to reverse the anti-inflammatory effect of maprotiline by propranolol (10 mg kg(-1)), prazosin (4 mg kg(-1)), yohimbine (10 mg kg(-1)), naloxone (4 mg kg(-1)) and mifepristone (5 mg kg(-1)). RESULTS: Systemic, intracerebroventricular and subplantar application of maprotiline significantly inhibited peripheral edema, but intrathecal maprotiline did not alter the degree of paw swelling. The applied antagonists failed to change the anti-inflammatory activity of maprotiline. CONCLUSION: These results demonstrate that maprotiline has a potent anti-inflammatory effect and this effect is linked to the peripheral and supraspinal actions of the drug.

The antidepressants maprotiline and fluoxetine have potent selective antiproliferative effects against Burkitt lymphoma independently of the norepinephrine and serotonin transporters.

The discovery that some selective serotonin transporter- (SSRI) and norepinephrine transporter- (NSRI) targeting antidepressants have the potential to act as anticancer agents adds greatly to their diverse pharmacological application. We report that the SSRI fluoxetine and the NSRI maprotiline are potent antiproliferative agents against human Burkitt lymphoma (BL), having little effect on normal blood cells. The results of this study show that although there is low-level expression of the norepinephrine transporter (NET) in some BL cells, NET is not involved in fluoxetine- or maprotiline-mediated cell death, as neither norepinephrine nor other NET inhibitors prevented this death. Of other NET ligands investigated for activity, only desipramine was found to have a similar effect to maprotiline and fluoxetine, suggesting the existence of a common selective structural modality for cell death and aiding in the future development of more potent analogs. In this study, we also show evidence to support previous reports that the serotonin transporter (SERT) has no involvement in antidepressant-mediated cell death, as SERT-specific ligands were unable to prevent fluoxetine or maprotiline cell death and not all SERT ligands could induce cell death. Although no target has yet been identified for the action of these compounds, the cell death elicited is potent, selective, and worthy of future investigation.

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Effects of antidepressants maprotiline and fluxilan on sympatho-adrenomedullary system in stressed rats.

Influence of previous stress exposure on the effects of serotonergic and noradrenergic antidepressants on subsequent newly induced stress is still far from being completely understood. The aim of the present study was to investigate changes in the activity of the sympatho-adrenomedullary system in unstressed and chronic unpredictable mild stressed (CUMS) rats treated with either maprotiline or fluxilan, both under basal conditions and subsequent immobilization stress. Maprotiline and fluxilan elevated plasma norepinephrine in unstressed control and CUMS rats. Immobilization increased norepinephrine less in unstressed maprotiline- or fluxilan controls than in vehicle group. Subsequent immobilization elevated norepinephrine in CUMS rats the differences between the groups being insignificant. Maprotiline didn't affect epinephrine in unstressed and CUMS rats and fluxilan increased it. Subsequent immobilization elevated epinephrine in unstressed maprotiline controls less than in vehicle animals. Epinephrine increase was similar in maprotiline CUMS and vehicle CUMS rats. Immobilization of fluxilan unstressed and CUMS rats significantly increased epinephrine but without differences compared to vehicle group. Novel stressor activated sympatho-adrenomedullary system of CUMS rats upon antidepressants.

TMD chronic pain and masseter silent period in psychiatric patients on antidepressive therapy.

The aim of the study was to evaluate the long-term effects of antidepressive therapy on chronic pain and related disability, and masseter silent period in psychiatric depressive patients with temporomandibular disorders (TMD). The study included hospitalized psychiatric depressive patients on antidepressive therapy protocol (tetracyclic antidepressant-maprotiline and anxiolytic-diazepam) (n=30) and non-psychiatric patients seeking prosthodontic treatment (control group, n=38). TMD were diagnosed by Research Diagnostic Criteria for temporomandibular disorders proposed by Dworkin and LeResche. The surface electromyography was recorded from left and right masseter muscles and masseter inhibitory reflex (masseter silent period) was recorded after mechanical stimulation. The incidence of TMD appearance was very similar, of approximately 40% in both group of patients. The results of the study also indicated a higher prevalence of joint related TMD, a lower prevalence of muscular subtype of TMD and a lower grade of chronic pain and related disability in the psychiatric group of patients on antidepressive therapy in comparison with findings in the control group. In the patients on antidepressive therapy with TMD masseter silent period was not prolonged , while in the control group of patients with TMD the prolongation of the silent period was observed. The study provided evidence that long-term, combined therapy (maprotiline and diazepam) in psychiatric depressive patients significantly modulated signs and symptoms of TMD in comparison with the control group.

Comparisons of glucose-insulin homeostasis following maprotiline and fluoxetine treatment in depressed males.

BACKGROUND: To investigate the effects of antidepressants on glucose-insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization. METHODS: Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n=11, fluoxetine n=12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method. RESULTS: The HAM-D scores were reduced significantly (P<0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P=0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239+/-682 vs. 4698+/-597 pmol; P=0.04) during the FSIGT. LIMITATIONS: The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course. CONCLUSIONS: The results suggest that the beta-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity.

[Antidepressants with different action mechanisms in the treatment of chronic daily headache].

Efficacy and safety of the following antidepressants: amitryptiline (tricyclic antidepressant), escitalopram (selective inhibitor of serotonin reuptake), milnacipran (selective inhibitor of serotonin and noradrenalin reuptake) and maprotiline (selective inhibitor of noradrenalin reuptake) have been compared during the treatment of 120 patients with chronic daily headache. A positive effect was found for all drugs, in particular in the presence of depressive and anxiety symptoms. Most effective proved to be milnacipran and amitryptiline. Escitalopram and milnacipran were more tolerable and had less side-effects. The authors suggested that the combination of noradrenergic and serotoninergic components appears to be most effective in treatment of chronic daily headache.

[Clinical observation on effect of danzhi xiaoyao powder in treating depression].

OBJECTIVE: To observe the effect and side effect of Danzhi Xiaoyao powder (DXP) in treating depression. METHODS: A randomized controlled and double-blinded study was conducted in 63 cases of depression by divided them into the western medicine group (WMG, 31 cases) treated with maprotiline, and the Chinese medicine group (CMG, 32 cases) treated with DXP. The effect of therapy was evaluated before and at the 2nd, 4th and 6th week of the treatment with Hamilton's depressive scale (HAMD), self-rating depression scale (SDS), self-rating anxiety scale (SAS) and the scale for TCM syndrome and symptom differentiation (TCM-SSD), and the side-effect of therapy was assessed with Asberg side-effect scale as well. RESULTS: There was no significant difference between the two groups in scores of HAMD, SDS, SAS, and TCM-SSD. The markedly effective rate in CMG was 84% and in WMG 87%, showed no significance between them (P > 0.05). The scores of HAMD, SDS and SAS of both groups were remarkably lowered after therapy (P < 0.05). However, the score of Asberg in CMG was lower than that in WMG (P < 0.05). CONCLUSION: DXP shows the effect equivalent to that of maprotiline, but with obviously less side-effect.

[Placebo to antidepressant effects ratio by electroencephalographic data]. / Sootnoshenie platsebo-éffekta i deistviia antidepressantov po dannym élektroéntsefalografii.

An analysis of EEG spectral characteristics of placebo effect and antidepressant (fluoxetine, maprotiline) monotherapy in patients with mild or moderate depressive episodes (ICD-10) has been conducted. Depending on clinical effects of placebo and antidepressants, the groups of placebo- and medication-responders/non-responders were compared. Placebo caused both particular and similar with the action of a single antidepressant dose changes in spectral power of EEG bands, which reduced during the pharmacotherapy course. The EEG changes achieved a significant level mostly in placebo-responders. Differences in EEG reactions between medication responders and non-responders were rare and emerged at the stage of the placebo therapy and single antidepressant dose intake. The change of between-hemisphere asymmetry of alpha-rhythm low band power in the frontal brain regions corresponding to the increase of activation of these regions in the left hemisphere, was found to be characteristic of thymoleptic effect of pharmacotherapy.