Aminoglycoside antibiotics remain indispensable despite their ototoxicity. Like other sensorineural forms, aminoglycoside-induced hearing loss (AGIHL) has no effective pharmacotherapy. Oxidative stress, apoptosis, excitotoxicity and inflammation are key pathological factors of the disease. We hypothesised that selegiline, an irreversible monoamine oxidase-B (MAO-B) inhibitor used in Parkinson’s disease, could be repurposed as an otoprotective agent against AGIHL and its effect on dopamine (DA) release from lateral olivocochlear (LOC) fibres, the efferent division of a protective feedback loop plays a major role in the protection against excitotoxicity. Selegiline mitigated AGIHL in BALB/c mice in a dose-dependent manner at different auditory brainstem response frequencies, including 16 kHz, the hearing sensitivity optimum of the animals. It also enhanced the action potential-evoked DA release from LOC efferents in mouse cochlear preparation dose-dependently. Inhibition of DA reuptake contributed to its basic effect of saving DA from metabolism. Among four selegiline analogues tested, the one that increased LOC DA release also provided otoprotection. In contrast, neither safinamide (a reversible MAO-B inhibitor) nor LJP-1207 (a selective semicarbazide-sensitive amine oxidase/vascular-adhesion protein 1 (SSAO/VAP1) inhibitor) prevented AGIHL, despite their antioxidant and anti-inflammatory properties. The reversibility or lack of MAO-B inhibition in safinamide and LJP-1207, respectively, as well as the absence of the propargylamine moiety with known intrinsic neuroprotective activity in both molecules, may explain their ineffectiveness. Selegiline, or certain propargylamine analogues of it, offer a promising therapy against AGIHL by addressing its multifactorial pathology through antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory actions, while enhancing endogenous DAergic protective mechanisms.

Neuropathic pain (NP), a disease affecting the somatosensory nervous system, causes a high socioeconomic burden on healthcare systems and society; yet, its management has not been fully solved. Post COVID-19, with sequelae of the somatosensory system, further increases the number of individuals with chronic pain, thus further exacerbating the social burden related to NP. The pro-inflammatory mediators, such as TNF-α, IL-1β, and IL-6, are massively released in patients with COVID-19 and are known to be involved in the pathomechanisms of NP, particularly in relation to neuronal sensitization. Specifically, the release of large amounts of these pro-inflammatory cytokines from immune and non-immune effector cells during the acute and post COVID-19 phases prone to have substantial involvement in the development of post COVID-19 NP. Several preclinical and clinical studies have shown that vitamins' supplementation, namely vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, and K can attenuate the enhanced release of TNF-α, IL-1β, and IL-6. The early supplementation of these vitamins may mitigate the neuronal sensitization evoked by cytokine storm due to COVID-19 or other viruses. This strategy may provide a novel approach to prevent the development of post COVID-19 NP. This review highlights the mechanisms by which COVID-19 can induce NP and how vitamins may help to alleviate these post COVID-19 sequelae.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson’s disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10−10–10−9 mol/L concentrations. Rasagiline added in 10−13 to 10−5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10−9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10−8–10−7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (−)methamphetamine (10−9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15–45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.

Pharmaceutically available enhancer selegiline/(-)-deprenyl (DEP) in the clinically used dose shows antidepressant effect, but nothing is known about this effect in enhancer dose, and its effect on co-morbid anxiety. Moreover, data about the antidepressant/antianxiety effects of the serotonin-influencing enhancer, (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) are also missing. The aim of the present paper is to establish the role of enhancer regulation in anxiety and follow the changes in the phosphorylation of glutamate subunits in prefrontal cortex as well as stress-related organ and hormonal changes as possible background mechanism. The effect of 3-week-treatment of rats with specific (0.001 mg/kg for DEP, 0.0001 mg/kg for BPAP) and non-specific (0.1 mg/kg for DEP, 0.05 mg/kg for BPAP) enhancer doses were evaluated on anxiety-like behavior in the elevated plus maze (EPM) and open-field (OF) tests. Phosphorylated glutamatergic GluR1 and GluN2B subunits were analyzed by Western blot. Changes in the stress-regulatory system were evaluated by measuring the organ weights and blood corticosterone concentrations. Non-specific enhancer doses had a tendency for anxiolysis on EPM, while only 0.1 mg/kg DEP elevated motility in OF. Specific enhancer doses significantly increased the expression of both glutamatergic receptor subunits; non-specific doses elevated only pGluR1. Treatments had no effects on stress-like organ weights; however, the specific enhancer doses significantly reduced the dark phase resting corticosterone levels. The study proved the enhancer-sensitivity of the glutamatergic transmitter system and suggested enhancer-induced stabilization of stress-hormone levels without major impact on non-stimulated anxiety-like behavior.

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

It has been hypothesized that α2-adrenoceptors (α2-ARs) may be involved in the pathomechanism of colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to α2-AR agonists. Therefore, we aimed to analyze the role of α2-ARs in acute murine colitis. The experiments were carried out in wild-type, α2A-, α2B-, and α2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2%); alpha2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels, or histologic score. Clonidine induced similar changes in α2B- and α2C-AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in α2A-AR KO animals. In contrast, selective inhibition of α2A-ARs by BRL 44408 significantly delayed the development of colitis; reduced the colonic levels of MPO and chemokine (C-C motif) ligand 3, chemokine (C-X-C motif) ligand 2 (CXCL2), CXCL13, and granulocyte-colony stimulating factor; and elevated that of tissue inhibitor of metalloproteinases-1. In this work, we report that activation of α2-ARs aggravates murine colitis, an effect mediated by the α2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.

We have synthesized a novel series of N-substituted sarcosines, analogues of NFPS (N-[3-(biphenyl-4- yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine), as type-1 glycine transporter (GlyT-1) inhibitors. Several compounds incorporated a diazine ring inhibited recombinant hGlyT-1b expressed permanently in CHO cells and GlyT-1 in rat brain synaptosomal preparations. A structure-activity relationship for the newly synthesized compounds was obtained and discussed on the ground of their GlyT-1 inhibitory potencies. Replacement of the biphenyl-4-yloxy moiety in NFPS with a 5-pyridazinylphenoxy moiety (compounds 3, 4, 5, and 6) or a 2-phenyl-5- pyridazinyloxy moiety (compounds 10, 11, and 12) afforded compounds exhibiting potent inhibition on GlyT-1 activity. The GlyT-1 inhibitory properties of NFPS analogues, in which sarcosine was closed into a ring forming (methylamino)pyridazine-3-(2H)-one, were markedly reduced (compounds 13 and 14). The pyridazine-containing GlyT-1 inhibitors with in vitro GlyT-1 inhibitory potency also enhanced extracellular glycine concentrations in conscious rat striatum as was measured by microdialysis technique. In contrast to NFPS, sarcosine-based pyridazine containing GlyT-1 inhibitors failed to evoke compulsive running behavior whereas they inhibited phencyclidine- induced hypermotility in mice. It is believed that increase of extracellular concentrations of glycine by inhibition of its reuptake may probably influence positively glutamate N-methyl-D-aspartate (NMDA)-type ionotropic receptors in the central nervous system. This may have importance in the treatment of neuropsychiatric disorders associated with hypofunctional NMDA receptor-mediated glutamatergic neurochemical transmission. Thus, impaired NMDA receptor functions have been shown to be involved in the development of the negative symptoms and the cognitive deficit of schizophrenia and the treatment of these symptoms is the possible clinical indication of GlyT-1 inhibitors including those containing pyridazine moiety.

Opioids are among the world's oldest known drugs used mostly for pain relief, but recreational use is also widespread. A particularly important problem is opioid exposure in females, as their offspring can also be affected. Adverse intrauterine and postnatal environments can affect offspring development and may lead to various disabilities later in life. It is clear that repetitive painful experiences, such as randomly occurring invasive procedures during neonatal intensive care, can permanently alter neuronal and synaptic organization and therefore later behavior. At the same time, analgesic drugs can also be harmful, inducing neuronal apoptosis or withdrawal symptoms in the neonate and behavioral alterations in adulthood. Hence, risk–benefit ratios should be taken into consideration when pain relief is required during pregnancy or in neonates.Recreational use of opioids can also alter many aspects of life. Intrauterine opioid exposure has many toxic effects, inducing poor pregnancy outcomes due to underdevelopment, but it is believed that later negative consequences are more related to environmental factors such as a chaotic lifestyle and inadequate prenatal care. One of the crucial components is maternal care, which changes profoundly in addicted mothers. In substance-dependent mothers, pre- and postnatal care has special importance, and controlled treatment with a synthetic opioid (e.g., methadone) could be beneficial.We aimed to summarize and compare human and rodent data, as it is important to close the gap between scientific knowledge and societal policies. Special emphasis is given to gender differences in the sensitivity of offspring to perinatal opioid exposure.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. For more effective therapy early diagnostic markers could be beneficial. Therefore we compared one year old rats with adults and examined if changes in possible brain markers of AD preceeded memory decline. We also tested if vasopressin-deficient animals were useful model of AD as vasopressin has well known positive effect on memory and AD patient has decreased vasopressin production. We compared adult (3 month) and old (12 month), normal and vasopressin-deficient Brattleboro rats. To receive a comprehensive picture about their memory we examined their social discrimination, object discrimination and conditioned learning abilities (shuttle box). Amyloid precursor protein (APP), mitogen-activated protein kinase 1 (MAPK1), β-actin and tryptophan 2,3-dioxygenase 2 (TDO2) mRNA levels was measured by quantitative PCR. There was no difference between the memory of adult and aged groups. The vasopressin-deficient rats at both ages showed a weaker performance in the course of social and object discrimination tests and a higher escape failure during the shuttle box experiment. The brain marker mRNAs of the elder animals were higher than the levels of the adults, but the absence of vasopressin had no influence on them. Thus, the one year old rats showed elevated levels of AD-related markers, but memory deficits were observable only in vasopressin deficient animals. Vasopressin does not seem to have pathogenic role in AD. Changes in the studied markers might predict later symptoms, although further studies are required for confirmation.

UNLABELLED:Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically.OBJECTIVE:The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats.METHODS:Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment.RESULTS:Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen.CONCLUSION:Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid-exposed offspring short- and long-term behavioural disturbances can be detected which is well-known from literature. Besides direct pharmacological effects of morphine impaired maternal responsiveness and pup care could play a role in these disturbances.

This study describes the antinociceptive effects of μ-opioid agonists, d-Ala2,N-Me-Phe4,Gly5-ol-enkephalin (DAMGO) and morphine in a model of rat visceral pain in which nociceptive responses were triggered by 2% acetic acid intraperitoneal (i.p.) injections. DAMGO and morphine were administered i.p., to the same site where acetic acid was delivered or intracerebroventricularly (i.c.v.). The antinociceptive actions of i.p. versus i.c.v. administered DAMGO or morphine were evaluated in the late phase of permanent visceral nociceptive responses. Both compounds inhibited the nociceptive responses in a dose-dependent manner and exhibited more potent agonist activity after i.c.v. than i.p. administration. DAMGO and morphine showed comparable ED50 values after i.p. injections. However, DAMGO was much stronger than morphine after central administration. Co-administration of the peripherally restricted opioid antagonist, naloxone methiodide (NAL-M), significantly attenuated the antinociceptive effects of i.p. DAMGO or morphine. On the other hand, i.c.v. injections of NAL-M partially antagonized the antinociceptive effect of i.p. morphine and failed to affect the antinociceptive action of i.p. DAMGO indicating the partial and pure peripheral antinociceptive effects of morphine and DAMGO, respectively. These results suggest the role of either central or peripheral μ-opioid receptors (MOR) in mediating antinociceptive effects of i.p. μ-opioid agonists in the rat late permanent visceral pain model which closely resembles the clinical situation.

A fajdalom terapiajanak megoldasa surgető es relevans igeny. Korabban publikaltunk nehany az agyba limitaltan penetralo morfinant. Jelen munkaban kb. 30 uj szarmazekot vizsgaltunk. Periferias vs centralis analgetikus aktivitasuk 40-400, a rosszul penetralo opioid antagonistak gatoljak hatasukat, intrinsic efficacy-juk magas (periferias hatekonysag markere az altalunk kidolgozott modszer szerint ), gatlo hatasuk patkany DRG sejteken periferias tamadaspont mellett szol. Morfintolerans egerben spinalisan adva a DPDPE gatolja, mig TIPPszi potencirozza a DAMGO antinociceptiv hatasat. Patkanyon mind naiv mind tolerans allatban a hatas potencirozo. A prodynorfin genexpresszio es dinorfin szint a dependenciaert felelős agyi regiokban modosul periferias opioidok hatasara. A perinatalisan drog expozicionak kitett patkany anyak korai adoleszcens koru utodainak testsulya, adaptacios kepessege szignifikansan csokkent, erőltetett uszas teszten depressziot jeleztek, fizikalisan dependensekke, vulnerabilissa valtak. Az anyai viselkedes romlott. Konkluzio: uj morfinanok segitsegevel a C-6 szubsztitucio prominens szerepet demonstraltuk a periferias hatekonysag erősodeseben, a preemptiv analgeziaban, limitalt legzesdepresszio es pszichologiai dependencia mellett. Az eredmeny elmeleti jelentősege mellett gyakorlati fontossagu a klinikum szamara. Kimutattuk tovabba, hogy perinatalisan stimulans ill. opioid kabitoszerekkel kezelt patkanyok utodai vulnerabilissa valnak, az abuzus veszelye nő. | There is a permanent and relevant need to manage pain. Previously we published opioids with limited access to the brain. 30 new derivatives were studied in rodents and found to be more potent analgesics, than morphine (Mo). Their peripheral vs central activites were between 40-400, the analgesic action was inhibited by poorly penetrating antagonists contrast to Mo, they block DRG cells, their intrinsic efficacy (a good marker of peripheral activity), is much higher than Mo assessed by a method elaborated by us, suggesting a peripheral site of action. DPDP administered spinally to Mo tolerant mice inhibited, while TIPPsi potentiated DAMGO analgesia.. We observed potentiation both in naive and tolerant rat. Prodynorphin gene expression and dynorphin level in brain regions responsible for the development of dependence were modified by opioids. The body weight, the adaptive behaviour of early adolescent offspring of perinatally Mo and ecstasy exposed dams decreased, they show depression in swimming test, they became physically dependent, and vulnerable to addiction. The maternal behavior of dams was disturbed. Conclusion: new data on the mechanisms of preemptive analgesia were obtained by new C-6 substituted morphinans. Respiratory depression and psychological dependence were limited. This finding beside its basic importance has practical importance too.Furthermore the offspring of dams perinatally exposed to substances of drug abuse became vulnerable and prone to be addict..

Opioids impair the maternal behaviour of rats. The effect of morphine on maternal behaviour in dams treated chronically with morphine during the whole pregnancy and lactation has not been analysed systematically. The aim of the present study was to investigate the possible differences in the disruptive effect of morphine on maternal behaviour following morphine challenges between dams treated chronically with saline or morphine during gestation and postpartum. The antinociceptive action of morphine was also studied in dams. The disruptive effect of morphine on maternal behaviour was not changed as the postpartum period passed. The duration of this effect of morphine lasted for about 2h. The dose-dependent disruptive effect of acute doses of morphine on maternal behaviour was more marked in the morphine-treated dams, than in the saline-treated ones, indicating a tendency for sensitisation to this effect. A trend for tolerance was observed to the antinociceptive effect of morphine in animals treated daily with morphine during the entire gestational and lactation periods; however, this difference did not reach statistical significance. Our experimental protocol might be a predictive model of human opioid abuse. Sensitisation to the impairing effect of opiates on maternal behaviour may explain why a mother abusing heroin neglects her baby even if she does not experience euphoria.