Treating Guilt-Inducing Self-Talk in Ocd with Dramatized Socratic Dialogue: A Step by Step Intervention.

Objective: Fear of moral guilt and conseque:nt increased attention to personal actions and intentions are the main ingredients of the self-criticism in patients suffering from obsessive-compulsive disorder (OCD). This pathogenic attitude takes shape in a typical guilt-inducing self-talk.The purpose of this work is to describe in detail a novel cognitive therapeutic procedure for OCD called "Dramatized Socratic Dialogue" (DSD). Method: DSD is a theory-oriented intervention that combine elements of Socratic dialogue, chairwork, and cognitive acceptance strategies derived from Mancini's model, which posits that obsessive-compulsive (OC) symptoms stem from a fear of deontological guilt. Results: DSD appears to have many strengths, being a theory-oriented treatment and focusing, as a therapeutic target, on the cognitive structures that determine pathogenic processes and OC symptoms. Furthermore, it is a short, flexible and tailor-made intervention. Conclusions: Detailed description of the intervention could foster future research perspectives and thus be used in evidence-based effectiveness studies to establish whether DSD reduces OC symptoms and to investigate its mechanism of action.

Noninvasive screening of ocular surface disease in otherwise healthy patients scheduled for cataract surgery.

PURPOSE: To evaluate prevalence and characteristics of pathological ocular surface findings in healthy patients undergoing cataract surgery using a noninvasive ocular surface workup and a validated questionnaire. DESIGN: Prospective single-centre study (sub-analysis clinical trial no. NCT05754437). METHODS: Healthy patients undergoing senile cataract surgery were screened preoperatively by Oculus Keratograph (K5 M; Oculus GmbH, Wetzlar, Germany) for the evaluation of tear meniscus height (TMH), non-invasive keratograph break-up time (NIKBUT), and meibomian gland dropout. Ocular discomfort symptoms were scored by ocular surface disease index (OSDI) questionnaire. RESULTS: 120 eyes of 120 patients (62 females, 58 males; mean age 73.85 years, range 47-91 years) were included. All patients had at least 1 abnormal finding, while 19 (15.8%; 95% CI [0.09-0.22]) had alterations of all parameters. In detail, 39 patients (32.5%; 95% CI [0.24-0.41]) had pathological TMH (mean 0,15 mm [0.03 SD]), 102 (85%; 95% CI [0.79-0.91]) had pathological NIKBUT (mean 3.64 s [2.63 SD]), 117 (97.5%; 95% CI [0.95-1]) had some degree of gland dropout (mean 1.62 [0.70 SD]), 78 patients (65%; 95% CI [0.56-0.74]) had pathological OSDI scores (mean 28.63 [15.08 SD]). Using TFOS DEWS II criteria, 66 patients (55%; 95% CI [0.42-0.60]) resulted affected by dry eye. CONCLUSIONS: This quick noninvasive screening documented the high prevalence of pathological ocular surface parameters in patients without risk factors or previous diagnosis of dry eye who are scheduled for cataract surgery.

Ozonated Oil in Liposome Eyedrops Reduces the Formation of Biofilm, Selection of Antibiotic-Resistant Bacteria, and Adhesion of Bacteria to Human Corneal Cells.

The recent attention to the risk of potential permanent eye damage triggered by ocular infections has been leading to a deeper investigation of the current antimicrobials. An antimicrobial agent used in ophthalmology should possess the following characteristics: a broad antimicrobial spectrum, prompt action even in the presence of organic matter, and nontoxicity. The objective of this study is to compare the antimicrobial efficacy of widely used ophthalmic antiseptics containing povidone-iodine, chlorhexidine, and liposomes containing ozonated sunflower oil. We determined the minimum inhibitory concentration (MIC) on various microbial strains: Staphylococcus aureus (ATCC 6538), methicillin-resistant Staphylococcus aureus (ATCC 33591), Staphylococcus epidermidis (ATCC 12228), Pseudomonas aeruginosa (ATCC 9027), and Escherichia coli (ATCC 873). Furthermore, we assessed its efficacy in controlling antibiotic resistance, biofilm formation, and bacterial adhesion. All three antiseptic ophthalmic preparations showed significant anti-microbicidal and anti-biofilm activity, with the liposomes containing ozonated sunflower oil with the highest ability to control antibiotic resistance and bacteria adhesion to human corneal cells.

The Role of Childhood Experiences in the Development of Disgust Sensitivity: A Preliminary Study on Early Moral Memories.

Objective: Disgust is a basic emotion evolved to safeguard our omnivorous species from contagion. Although the factors eliciting disgust typically involve concerns related to physical contamination, physical disgust responses are also prompted by moral transgressions, (i.e. cannibalism, pedophilia, betrayal). The link between the general propensity to experience disgust (i.e. "Disgust Sensitivity") and morality, in particular in the deontological domain, is supported by an increasing amount of data on clinical and non-clinical sample. Evolutionistic explanations of this link posit that disgust evolved to indicate the presence of a threat to the integrity of the individual not only in the physical domain but also in the social and moral domain.In addition to the evolutionary point of view, this link could also be better investigated in terms of individual development. To the best of our knowledge, literature is scarce regarding which early experiences are associated to high DS. Therefore, this study aims to explore the content of early memories associated with disgust. Based on the strict link between disgust and morality, we hypothesized an association between DS and early memories of moral criticism. Method: 60 non-clinical participants filled in measures of DS. They were then presented with an auditory disgust induction, after which they recalled early memories through the technique of the "affect bridge". 10 independent raters assessed the emotional content of the memories on visual-analogical scales. Results: Results showed a positive association between disgust sensitivity and the propensity to experience deontological guilt. There was also a significant positive association between disgust sensitivity and moral memories, in particular relating to early experiences of being the object of contempt, moral criticism, anger, and of being held responsible. Conclusions: These data directly support the centrality of early morally-loaded interpersonal experiences in the development of DS, confirming the link between disgust and morality also at the level of individual historical development.

MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity.

Makorin ring finger protein 3 (MKRN3) was identified as an inhibitor of puberty initiation with the report of loss-of-function mutations in association with central precocious puberty. Consistent with this inhibitory role, a prepubertal decrease in Mkrn3 expression was observed in the mouse hypothalamus. Here, we investigated the mechanisms of action of MKRN3 in the central regulation of puberty onset. We showed that MKRN3 deletion in hypothalamic neurons derived from human induced pluripotent stem cells was associated with significant changes in expression of genes controlling hypothalamic development and plasticity. Mkrn3 deletion in a mouse model led to early puberty onset in female mice. We found that Mkrn3 deletion increased the number of dendritic spines in the arcuate nucleus but did not alter the morphology of GnRH neurons during postnatal development. In addition, we identified neurokinin B (NKB) as an Mkrn3 target. Using proteomics, we identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as another target of MKRN3. Interactome analysis revealed that IGF2BP1 interacted with MKRN3, along with several members of the polyadenylate-binding protein family. Our data show that one of the mechanisms by which MKRN3 inhibits pubertal initiation is through regulation of prepubertal hypothalamic development and plasticity, as well as through effects on NKB and IGF2BP1.

Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination.

CONTEXT: Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. OBJECTIVE: This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. METHODS: Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. RESULTS: Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. CONCLUSION: MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.

Unhealthy mind in a healthy body: A criticism to eliminativism in psychopathology.

In this article we criticize the thesis "The diseases we treat are diseases of the brain". A first criticism is against the eliminativist perspective and in favor of a perspective that is still reductionist but emergentist and functionalist. In a second part, we try to answer the question "under which conditions can we consider this statement legitimate?". We argue that only those mental disorders whose neural substrate has clearly neuropathological characteristics, i.e., anomalies with respect to the laws of good neural functioning, can be considered "brain diseases." We propose that it is not sufficient to observe a simple difference between the brains of people with psychopathology, that is, with anomalies with respect to the laws of good psychological functioning, and that of people without psychopathology. Indeed, we believe it is a categorical error to postulate a neuropathology starting from a psychopathology. Finally, we summarize some research that shows how purely psychological interventions can reduce or eliminate the differences between the brains of people with or psychopathology and those of people without.

Guilt Feelings in Obsessive Compulsive Disorder: An Investigation between Diagnostic Groups.

Guilt plays a role in various forms of psychopathology. However, different types of guilt might be involved in different mental disorders. Obsessive-compulsive (OC) patients are prone to a type of guilt in which the violation of an internalized moral norm is necessary and sufficient, whereas data suggest that depression might be linked to more interpersonal types of guilt. However, the extent to which a specific guilt phenomenology is involved in each condition is yet to be determined. Here we assessed the association between different types of guilt and different diagnostic groups. Two clinical samples (33 OCD and 35 non-OCD) filled in the Moral Orientation Guilt Scale (MOGS) along with other OCD and depression measures. Regression was employed to test group differences in the MOGS subscales and to test the influence of MOGS subscales on OCD and depression levels. Results confirm that different types of guilt might be implicated in different psychopathological conditions. Specifically, moral norm violation guilt is more present in OC patients than in other disorders. Depression seems to be associated with different guilt feelings depending on the psychopathological condition, specifically in non-OC patients, with types of guilt involving a "victim", supporting the accounts viewing interpersonal guilt as involved in the emergence of depressive symptomatology and hyper-altruistic behavior as a vulnerability factor for depression.

Group Imagery Rescripting on Childhood Memories Delivered via Telehealth: A Preliminary Study.

Background: Imagery Rescripting (ImR) has proved to be effective in the treatment of different mental disorders as an integral part of broader clinical protocols or as a standalone technique. ImR has also been successfully incorporated as part of group Schema Therapy treatment; however, to the best of our knowledge, it has never been assessed as a standalone technique in a group setting. Aim: In this study, we focused on ImR delivered via telehealth in groups and we aimed to assess whether group ImR is effective in responding to basic emotional needs, in changing participants' affective state, and in reducing dysfunctional beliefs. We also wanted to assess whether memory realism is associated with a greater effectiveness of the technique. Methods: A total of 52 participants were presented with 3 ImR sessions on childhood memories related to the current dysfunctional belief that elicited more suffering. Results: The technique was effective in facilitating the retrieval of a memory in almost the entire sample (in the range of 92.3-100%). Overall, memory realism values (level of vividness, ability to immerse, and participants' distance from the images) were high in all three sessions. Almost all participants were reported having their needs met during ImR (89.7%). Importantly, need satisfaction was associated with the ability to immerse in the image. In addition, the intensity of the dysfunctional belief decreased significantly from pre-test to Session 3. The technique also changed the affective state, reducing arousal. Importantly, we also observed a general reduction in shame levels from the first to the third session. Conclusion: A telehealth delivered ImR group intervention on childhood memories provides cognitive and emotional improvement. Along with the ability to satisfy the patient's basic emotional needs, the technique seems to be effective in modifying maladaptive beliefs encapsulated in memory.

Maternal serum eye drops to treat bilateral neurotrophic keratopathy in congenital corneal anesthesia: Case report and literature review.

PURPOSE: To report the feasibility and the successful outcomes of a pediatric neurotrophic keratopathy (NK) owing to congenital corneal anesthesia (CCA) treated with allogeneic serum eye drops obtained from the mother as the only therapy. OBSERVATIONS: A 18-month-old girl with generalized pain insensitivity presented with a large epithelial defect in the right eye (RE) and superficial punctate keratopathy (SPK) in the left eye (LE). Corneal sensitivity was completely absent in both eyes (BE). Peripheral serum eye drops obtained from the mother was prescribed and administered every 2 hours in BE. Two weeks after the beginning of treatment, compete healing of the epithelial defect in the RE was obtained, while the severity of the SPK in the LE markedly improved; in parallel, conjunctival hyperemia disappeared in BE. The treatment was continued over the course of 3 months with good tolerability and neither signs of recurrence of the epithelial defect nor other complications were noted. CONCLUSIONS AND IMPORTANCE: Allogeneic serum eye drops obtained from the mother are effective in treating pediatric NK owing to CCA. This treatment may represent a readily available and inexpensive option when topical nerve growth factor is unavailable or corneal neurotization is not feasible.

Genetics of pubertal timing.

Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Pubertal onset is regulated by genetic, nutritional, environmental, and socio-economic factors. Disturbances affecting pubertal timing result in adverse health conditions later in life. Human genetic studies show that around 50-80% of the variation in pubertal onset is genetically determined. The genetic control of pubertal timing has been a field of active investigation in attempt to better understand the neuroendocrine control of this relevant period of life. Large populational studies and patient cohort-based studies have provided insights into the genetic regulation of pubertal onset. In this review, we discuss these discoveries and discuss potential mechanisms for how implicated genes may affect pubertal timing.

Deontological Guilt and Disgust Sensitivity Modulate Moral Behaviour.

OBJECTIVE: Deontological Guilt (DG), and Altruistic Guilt (AG) emerge from the appraisal of violating an internalized rule or an altruistic principle, respectively. DG is strictly connected with Disgust Sensitivity and plays a key role in the development and maintenance of Obsessive-Compulsive Disorder (OCD). Previous studies investigated how DG affects responses to hypothetical moral dilemmas, however how DG and Disgust Sensitivity interact modulating moral behavior is still unknown. METHODS: STUDY 1. 46 healthy participants performed an ecological paradigm in which people can spontaneously decide to lie to obtain a reward (egoistic lie) or give it away (altruistic lie) after three emotional inductions: DG, AG or neutral. Furthermore, OCD traits, Morality, Guilt Propensity and Disgust Sensitivity were assessed by means of questionnaires. STUDY 2. 27 participants from the original sample were retested during the COVID-19 lockdown in Italy to ascertain whether the pandemic modified traits related to morality, disgust, guilt or OCD symptoms and whether these changes modulated moral behavior (measured by a task in which cheating was associated to higher pay-offs). RESULTS: STUDY 1. Compared to the neutral, after the DG induction participants produced less altruistic and more egoistic lies. This effect was stronger in participants with high Disgust Sensitivity. STUDY 2. During the COVID-19 lockdown participants became more sensitive to the Authority pillar of the Moral Foundations and more sensitive to Disgust: this increment in deontological morality affected (im) moral behavior depending on changes in Disgust Sensitivity. CONCLUSIONS: Our data suggest that people with high Disgust Sensitivity are more affected by deontological inductions which translate to higher immorality, supposedly by lowering their moral self-image. These results might have important clinical implications as they suggest that addressing Disgust Sensitivity in therapy, might also decrease the effect of guilt on patients' behavior.

Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty.

Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

New Perspectives in the Pathophysiology and Treatment of Pain in Patients with Dry Eye Disease.

Ocular discomfort and eye pain are frequently reported by patients with dry eye disease (DED), and their management remains a real therapeutic challenge for the Ophthalmologist. In DED patients, injury at the level of each structure of the ocular surface can determine variable symptoms, ranging from mild ocular discomfort up to an intolerable pain evoked by innocuous stimuli. In refractory cases, the persistence of this harmful signal is able to evoke a mechanism of maladaptive plasticity of the nervous system that leads to increased pain responsiveness. Peripheral and, subsequently, central sensitization cause nociceptor hyperexcitability and persistent pain perception that can culminate in the paradoxical situation of perceiving eye pain even in the absence of ocular surface abnormalities. Effective therapeutic strategies of these cases are challenging, and new options are desirable. Recently, a theoretical novel therapeutic approach concerns enkephalins thanks to the evidence that eye pain sensations are modulated by endogenous opioid peptides (enkephalins, endorphins and dynorphins). In this regard, new topical agents open up a new theoretical scenario in the treatment of ocular discomfort and eye pain in the setting of DED, such as, for example, a multimolecular complex based on proteins and glycosaminoglycans also containing opiorphin that may assist the physiological pain-relieving mechanism of the eye.

LGR4 deficiency results in delayed puberty through impaired Wnt/ß-catenin signaling.

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/ß-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/ß-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/ß-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.

DLK1/PREF1 marks a novel cell population in the human adrenal cortex.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.

Rescripting Memory, Redefining the Self: A Meta-Emotional Perspective on the Hypothesized Mechanism(s) of Imagery Rescripting.

Imagery Rescripting (ImRs) is a therapeutic technique that aims to reduce the distress associated with negative memories of early aversive experiences. It consists of prompting patients to rescript the autobiographical memory in line with their unmet needs. In recent years, ImRs was found effective in reducing symptoms of disorders such as depression, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and personality disorders. However, the cognitive mechanisms underlying such broad effectiveness are currently an object of debate. Empirical evidence has shown that ImRs reduces the negative self-belief derived from aversive memories in different types of mental disorders. However, existing accounts are not very accurate in explaining how this change in self-belief occurs and therefore why ImRs is effective across psychopathologies. We propose that ImRs changes the semantic self-representation encapsulated in the aversive memory by reducing the meta-emotional problem (i.e., perceiving a negative emotion as problematic and unacceptable). Empirical evidence implicates the meta-emotional problem or "secondary problem" in the maintenance of different disorders and has shown that treating it leads to symptoms reduction. Here we hypothesize that: (i) ImRs as a stand-alone treatment may lead to a reduction of symptoms; negative self-belief and the meta-emotional problem; and (ii) the reduction of the meta-emotional problem might mediate the relation between symptoms and negative self-belief reduction. To test our hypothesis, we present an experimental procedure that could be used in future studies. We conclude discussing the existing theoretical frameworks that attempt to unravel the mechanisms that play a role in ImRs.

Synthesis and biological evaluation of a new class of benzothiazines as neuroprotective agents.

Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na+ and Ca2+-channels, showing a profile comparable with that of 1.