Neurosteroids are important regulators of central nervous system function and may be involved in processes of neuronal cell survival. This study was undertaken to test the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL), pregnenolone sulfate (PGLS), and allopregnanolone (Allo) on hydrogen peroxide- and staurosporine-induced toxicity in SH-SY5Y cells. It has been found that DHEAS inhibited the hydrogen peroxide toxicity in a concentration-dependent manner, whereas DHEA was active only at higher doses. PGL and PGLS showed neuroprotective effects only at the lowest concentration. Allo had no significant effect on hydrogen peroxide-evoked lactate dehydrogenase release and at the highest concentration aggravated its toxic effects. Next part of this study evaluated neurosteroid effects on staurosporine-induced apoptosis. DHEAS, DHEA, and PGL significantly antagonized effects of staurosporine on both caspase-3 activity and mitochondrial membrane potential. PGLS and Allo inhibited the staurosporine-induced changes in both apoptotic parameters only at the lowest concentration. Antiapoptotic properties of neurosteroids were positively verified by Hoechst staining. Furthermore, as shown by calcein assay, DHEA, DHEAS, and PGL increased viability of staurosporine-treated cells, and these effects were attenuated by specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated protein kinase (ERK)-mitogen activated protein kinase (MAPK). These data indicate that neurosteroids prevent SH-SY5Y cell damage related to oxidative processes and activation of mitochondrial apoptotic pathway. Moreover, neuroprotective effects of DHEA, DHEAS seem to depend on PI3-K and ERK/MAPK signaling pathways. It can be suggested that, at physiological concentrations, all studied neurosteroids participate in the inhibition of neuronal apoptosis, but with various potencies.

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(2014) 'Analgesic eects of antidepressants alone and after their local co-administration with morphine in a rat model of neuropathic pain.', Pharmacological reports., 66 (3). pp. 459-465. Further information on publisher's website: Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. IntroductionNeuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [1]. The most frequent etiologic factors of neuropathic pain are trauma (including post-surgery scars), metabolic disturbances (e.g., diabetes mellitus) and ischemia. The pathological mechanism of neuropathic pain differs significantly from that of inflammatory pain; studies have shown that the changes in spinal gene expression under neuropathy and inflammations are different [2]. Thus, the response to antinociceptive drugs, especially opioids, is not the same. It has generally been accepted that neuropathic pain is somewhat resistant to morphine administration in clinical studies [3,4], and the reduced ability of morphine to attenuate allodynia and hyperalgesia in experimental models of neuropathic pain has been demonstrated [5][6][7][8]. For these reasons, it is a common clinical practice to use analgesic drug combinations. The primary approach to treat neuropathic pain is the use of coanalgesics such as tricyclic antidepressants (TCA); however, their systemic application is associated with significant side effects, which can hinder the desired analgesic effect. An alternative approach to this is the topical administration of analgesics. Currently, the possibility of the topical Background:The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. Methods: This study was performed on rats after chronic constriction injury (CCI) to the sciatic nerve. The von Frey and Hargreaves' tests were used to assess mechanical allodynia and thermal hyperalgesia, respectively, after intraplantar (ipl) or subcutaneous (sc) administration of amitriptyline, doxepin, or venlafaxine, or their ipl co-administration with morphine on day 12-16 after inj...

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