Neurotransmitter Reuptake Research Articles

Neuron-Glial Interactions: Implications for Plasticity, Behavior, and Cognition.

The traditional view of glial cells as mere supportive tissue has shifted, due to advances in technology and theoretical conceptualization, to include a diversity of other functions, such as regulation of complex behaviors. Astrocytes, the most abundant glial cells in the central nervous system (CNS), have been shown to modulate synaptic functions through gliotransmitter-mediated neurotransmitter reuptake, influencing neuronal signaling and behavioral functions. Contemporary studies further highlight astrocytes' involvement in complex cognitive functions. For instance, inhibiting astrocytes in the hippocampus can lead to memory deficits, suggesting their integral role in memory processes. Moreover, astrocytic calcium activity and astrocyte-neuron metabolic coupling have been linked to changes in synaptic strength and learning. Microglia, another type of glial cell, also extend beyond their supportive roles, contributing to learning and memory processes, with microglial reductions impacting these functions in a developmentally dependent manner. Oligodendrocytes, traditionally thought to have limited roles postdevelopment, are now recognized for their activity-dependent modulation of myelination and plasticity, thus influencing behavioral responses. Recent advancements in technology and computational modeling have expanded our understanding of glial functions, particularly how astrocytes influence neuronal circuits and behaviors. This review underscores the importance of glial cells in CNS functions and the need for further research to unravel the complexities of neuron-glia interactions, the impact of these interactions on brain functions, and potential implications for neurological diseases.

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5-/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments.

Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants

AbstractMost treatments to alleviate major depression work by either inhibiting human monoamine transporters, vital for the reuptake of monoamine neurotransmitters, or by inhibiting monoamine oxidases, which are vital for their degradation. The analysis of the experimental 3D structures of those antidepressants in their drug formulation state is key to precision drug design and development. In this study, microcrystal electron diffraction (MicroED) is applied to reveal the atomic 3D structures for the first time of five of the most prevalent antidepressants (reboxetine, pipofezine, ansofaxine, phenelzine, and bifemelane) directly from the commercially available powder of the active ingredients. Their modes of binding are investigated by molecular docking, revealing the essential contacts and conformational changes into the biologically active state. This study underscores the combined use of MicroED and molecular docking to uncover elusive drug structures and mechanisms to aid in further drug development pipelines.

Duloxetine protected indomethacin-induced gastric mucosal injury by increasing serotonin-dependent RANTES expression and activating PI3K-AKT-VEGF pathway

Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are the principal mediators of inflammation. Thus, by screening the differential expression of cytokines in the gastric mucosa using cytokine array at 3 h after indomethacin exposure, when the gastric ulcer began to format, we found that indomethacin increased cytokines which promoted inflammation responses, whereas duloxetine decreased pro-inflammatory cytokines increased by indomethacin and increased RANTES expression. RANTES was consistently increased by pretreated with both 5 mg/kg and 20 mg/kg duloxetine at 3 h and 6 h after indomethacin exposure in male rats. Selective blockade of RANTES-CCR5 axis by a functional antagonist Met-RANTES or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin (5-HT), norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased 5-HT levels in platelet-poor plasma, while treatment with 5-HT promoted expression of RANTES in the gastric mucosa and alleviated the indomethacin-induced gastric injury. Furthermore, duloxetine activated PI3K-AKT-VEGF signaling pathway, which was regulated by RANTES-CCR5, and selective inhibitor of VEGF receptor axitinib blocked the prophylactic effect of duloxetine. Furthermore, duloxetine also protected gastric mucosa from indomethacin in female rats, and RANTES was increased by duloxetine after 6 h after indomethacin exposure too. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in gastroprotective effect of duloxetine against indomethacin, which advanced our understanding in inflammatory modulation by monoamine-based antidepressants.

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

3,5-Dimethyladamantan-1-amine Restores Short-term Synaptic Plasticity by Changing Function of Excitatory Amino Acid Transporters in Mouse Model of Spinocerebellar Ataxia Type 1

Introduction. Memantine is an agent that used for treatment of Alzheimer's type dementia. Memantine considerably reduces the effects of neurodegeneration, may potentially slow down the neurodegenerative changes in the cerebellum and may act as treatment of choice for spinocerebellar ataxia type 1 (SCA 1).
 Our objective was to study molecular mechanisms of the short-term synaptic plasticity improvement associated with long-term memantine use in SCA 1 transgenic mice.
 Materials and methods. The experiments were performed on 12-week-old CD1 mice. We created a mouse model of cerebellar astrogliosis after expression of mutant ataxin-1 (ATXN1[Q85]) in the Bergmann glia (BG). To model the astrocyte-mediated neurodegeneration in the cerebellum, the mice were injected with LVV GFAP-Flag-ATXN1[Q85] lentiviral vector (LVV) constructs intracortically. Some of the mice received 0.35 mg/kg memantine dissolved in drink water once daily for 9 weeks. The control animals were administered LVV GFAP-ATXN1[Q2]-Flag. Changes of the excitatory postsynaptic currents amplitudes from Purkinje cells (PC) were recorded by patch clamp. Expression of anti-EAAT1 in the cerebellar cortex was assessed using immunohistochemistry.
 Results. The reactive glia of the cerebellar cortex in SCA1 mice is characterized by a decrease in the immunoreactivity of anti-EAAT1, while chronic memantine use restores this capacity. The decay time of the excitatory postsynaptic current amplitude in the parallel fiber-Purkinje cell (PF-PC) synapses of the SCA1 mice is considerably longer, which indicates the slowing of glutamate reuptake and EAAT1 dysfunction. The prolonged presence of increased neurotransmitter levels in the synaptic cleft facilitates activation of the mGluR1 signaling and restoration of mGluR1-dependent synaptic plasticity in Purkinje cells of the SCA1 mice.
 Conclusions. The slowing of neurotransmitter reuptake associated with long-term memantine treatment improves mGluR1-dependent short-term synaptic plasticity of the Purkinje cells in the SCA1 mice. Restoration of synaptic plasticity in these animals may underlie partial reduction of ataxic syndrome.

Terpenoids and Triterpenoid Saponins: Future Treatment for Depression

Background: Depression is a crippling mental disorder with high prevalence around the world. The available clinical antidepressants have been effective to a certain degree, and different side effects have limited their application. This leads to the necessity of finding new treatments. Herbal plants are a substantial source of new drug leads. Terpenoid compounds are secondary metabolites representing an enormous category of structures found commonly in plants either as aglycones or attached to sugar moieties. These phytochemicals have been extensively studied for their various biological effects, and several have been investigated for potential therapeutic effects in the treatment of depression. Aim: This review aims to highlight the current knowledge on some terpenoids and triterpenoid saponins as potential antidepressant agents and their mechanisms of action, which may provide a better understanding of the potential antidepressant-like effects of these compounds and lead to the development of auspicious molecules with high efficiency and low side effects for depressive disorders treatment. Methods: A total of 16 plants containing antidepressant agents are reviewed in this article. 9 terpenoids and 23 triterpenoid saponins compounds have been reported to becommonly found in plant extracts, indicating potential use for depression. To enhance the datum of this review, the mechanism of action for the candidate compounds has been predicted via functional enrichment analysis. Results: The behavioural and neurochemical effects, as well as the possible mechanisms of action, have been evaluated in rodents by different predictive models of depression, mainly the acute stress models of the forced swimming test (FST) and tail suspension test (TST). The involved mechanisms include enhancing monoamine neurotransmitters, ameliorating brain-derived neurotrophic factor (BDNF), and normalizing the hypothalamus-pituitary-adrenal (HPA) axis. Preclinical studies support the potential antidepressant activities of some terpenoid compounds. Furthermore, the functional enrichment analysis has confirmed the previous pre-clinical findings and predicted further mechanisms of action, including cellular calcium ion homeostasis, cellular response to dopamine, endocrine resistance, and regulating GABAergic, serotonergic, glutamatergic, and dopaminergic synapse, bedsides neurotransmitter reuptake. Conclusion: Terpenoids and triterpenoid saponins provide a large number of natural compounds. This review sheds light on terpenoids and triterpenoid saponins compounds with antidepressantlike activity and their potential mechanisms of action. However, more evaluations are required to confirm that these compounds are promising for discovering antidepressant drugs.

SLC6A1 patient & organization perspective: founding of SLC6A1 connect, research, and ongoing efforts.

This paper describes the founding of the SLC6A1 Connect organization, which offers resources to patients and families with SLC6A1 diagnoses while keeping current with a scientific overview of the disorder. Following the birth of her two lovely twins, Amber Freed noticed how her son, Maxwell, missed motor development milestones and would often stare. Eventually, these signs led to a diagnosis of an SLC6A1 variant. The SLC6A1 gene is located on the short arm of chromosome 3 and the gene encodes for the gamma-aminobutyric acid (GABA) transporter 1 (GAT-1) protein. This transporter is responsible for the reuptake of the inhibitory neurotransmitter, GABA. The transporter usually removes GABA from the synapse space between two neurons, limiting over-excitability in the brain, which can lead to seizures and motor deficits as Amber noticed in her son, Maxwell. Amber realized that there were nearly no treatment options for her son's condition so she began forming connections with scientists and doctors. Initially, she flew to see Dr. Steven Gray, with whom she developed a research plan for a gene replacement therapy to treat the variant along with a design for a clinical trial. Not only this but they needed to raise four million dollars to fund these endeavors. Freed founded the SLC6A1 Connect organization to raise money and awareness and put together a network of dedicated researchers and families. Since then, the organization has raised over two million dollars and grown to offer families a base of support. The organization even hosts a yearly symposium with families, scientists, and biotech or pharmaceutical companies worldwide. In addition, we detail how the organization now offers informational resources to families to help them understand the science behind the variant and ways to help their children such as registry links and genetic testing options. These endeavors have led the organization to collaborate with scientists based on institutions such as Vanderbilt University Medical Center, UT Southwestern Medical Center, the Cleveland Clinic, and many industrial pharmaceutical partners.

Equine grass sickness is associated with major abnormalities in the ultrastructure of skeletal neuromuscular junctions.

Equine grass sickness (EGS) is a frequently fatal multisystem neuropathy of equids. The aetiology is unknown; proposed causes include toxicoinfection with Clostridium botulinum and a mycotoxicosis. The effect of EGS on the organisation and structural integrity of the skeletal neuromuscular junction (NMJ), the target of botulinum neurotoxins (BoNTs), is unknown. To compare the organisation and structural integrity of skeletal NMJs from EGS horses, control horses and one horse with a presumptive diagnosis of botulism. Blinded, retrospective case control. NMJs in samples of diaphragm or intercostal muscle from six EGS horses, three control horses and one equine botulism case were compared using electron microscopy, morphometry and confocal light microscopy. A significantly higher percentage of EGS NMJs had abnormal morphology (EGS 72.2%, 95% CI 55.6-84.4; Controls 6.9%, 1.7-23.8; OR 35.1, 8.47-244.8; p < 0.001). EGS NMJs had a significantly lower mean volume fraction occupied by synaptic vesicles (SVs) (EGS 18.7%, 12.6-28.0; Controls 36.3%, 20.8-63.4; p = 0.024). EGS NMJs had evidence of accelerated SV exocytosis and SV depletion, accumulation of neurofilament-like material in terminal boutons and/or bouton degeneration. NMJs from the botulism horse had dense packing of SVs towards the presynaptic membrane active zone, consistent with BoNT intoxication, but had absence of the abnormalities identified in EGS NMJs. Group sizes were limited by difficulties obtaining suitably processed samples. Ages of control and EGS horses differed. Botulism was diagnosed based on clinical and post mortem findings. EGS is associated with major changes in skeletal NMJ ultrastructure that are inconsistent with the effects of BoNTs. SV depletion may reflect increased exocytosis coupled with reduced repopulation of SVs via anterograde axonal transport and endocytosis, consistent with the action of an excitatory presynaptic toxin and/or neurotransmitter reuptake inhibitor. Skeletal NMJs represent a previously unrecognised target for the toxin that causes EGS.

Mouse models for inherited monoamine neurotransmitter disorders.

Several mouse models have been developed to study human defects of primary and secondary inherited monoamine neurotransmitter disorders (iMND). As the field continues to expand, current defects in corresponding mouse models include enzymes and a molecular co-chaperone involved in monoamine synthesis and metabolism (PAH, TH, PITX3, AADC, DBH, MAOA, DNAJC6), tetrahydrobiopterin (BH4) cofactor synthesis and recycling (adGTPCH1/DRD, arGTPCH1, PTPS, SR, DHPR), and vitamin B6 cofactor deficiency (ALDH7A1), as well as defective monoamine neurotransmitter packaging (VMAT1, VMAT2) and reuptake (DAT). No mouse models are available for human DNAJC12 co-chaperone and PNPO-B6 deficiencies, disorders associated with recessive variants that result in decreased stability and function of the aromatic amino acid hydroxylases and decreased neurotransmitter synthesis, respectively. More than one mutant mouse is available for some of these defects, which is invaluable as different variant-specific (knock-in) models may provide more insights into underlying mechanisms of disorders, while complete gene inactivation (knock-out) models often have limitations in terms of recapitulating complex human diseases. While these mouse models have common phenotypic traits also observed in patients, reflecting the defective homeostasis of the monoamine neurotransmitter pathways, they also present with disease-specific manifestations with toxic accumulation or deficiency of specific metabolites related to the specific gene affected. This review provides an overview of the currently available models and may give directions toward selecting existing models or generating new ones to investigate novel pathogenic mechanisms and precision therapies.

Benefits of amitriptyline in relation to interstitial cystitis

Introduction: interstitial cystitis is a clinical syndrome characterized by increased urinary frequency and pelvic pain, primarily affecting women. Two phenotypes of this disease have been identified, each with a different mechanism. Proper diagnosis is essential, as it can be confused with a urinary tract infection. Amitriptyline, a tricyclic antidepressant, has shown benefits in the treatment of interstitial cystitis by acting on symptoms and improving patients' quality of life. Its mechanism of action includes blocking the reuptake of neurotransmitters associated with pain.Objectives: the main objective of this study is to review the main benefits of amitriptyline in relation to interstitial cystitis, analyzing its efficacy and safety.Methods: a literature review was conducted using the Prisma method. Clinical trials and systematic reviews addressing the benefits of amitriptyline in patients with interstitial cystitis were included.Results: after selecting 15 relevant articles, it was found that amitriptyline can reduce symptoms and improve the quality of life of patients with interstitial cystitis. Additionally, a significant improvement was observed in patients treated with amitriptyline compared to other treatments. Amitriptyline demonstrated an anti-inflammatory, nervous system modulating, and urodynamic effect in patients with interstitial cystitis.Conclusions: amitriptyline may be an effective and safe option in the treatment of interstitial cystitis, improving symptoms and quality of life for patients. It is suggested that this drug may act as a neuromodulator, anti-inflammatory, and urodynamic agent in patients with interstitial cystitis

ANALYSIS OF THE FUNCTIONAL STATE OF ASTROGLIA IN THE HIPPOCAMPUS OF RATS GENETICALLY PRONE TO AUDIOGENIC SEIZURES

It was shown that abnormalities in astrocyte functions can cause alterations in neuronal excitability and promote the development of epilepsy, however, this question claims further investigation. The aim of the present work was to analyze the functional state of astrocytes in the hippocampus of Krushinsky-Molodkina (KM) rats genetically predisposed to the reflex audiogenic seizures. Adult naïve animals with fully-established audiogenic sensitivity were recruited in our experiments. Rats of parental Wistar strain were used as a control. Obtained results revealed unchanged protein expression of such astocytic markers as GFAP, ALDH1L1, and NFIA suggesting the absence of the reactive astrogliosis in the hippocampus of KM rats. SPARC and aquaporin 4 expression also did not differ from the control indicating no violations in astroglia regulation of synaptogenesis and water balance. Analysis of glial proteins responsible for reuptake and metabolism of neurotransmitters revealed normal expression of GABA transporter GAT-3 and glutamine synthetase, while glutamate transporters EAAT1 and 2 were significantly elevated pointing on enhanced activity of glutamate removal from synapses. In addition, decreased expression of the key glycolytic enzyme aldolase C, probably, indicated insufficient activity of glucose metabolism in astrocytes. Thus, obtained data pointed on genetically determined alterations of astroglia functions in the hippocampus of rats with inherited reflex epilepsy.

Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

Lipid-dependent regulation of neurotransmitter release from sympathetic nerve endings in mice atria

Neurotransmitter release from sympathetic terminals is a key avenue for heart regulation. Herein, presynaptic exocytotic activity was monitored in mice atrial tissue using a false fluorescent neurotransmitter FFN511, a substrate for monoamine transporters. FFN511 labeling had similarity with tyrosine hydroxylase immunostaining. High [K+]o depolarization caused FFN511 release, which was augmented by reserpine, an inhibitor of neurotransmitter uptake. However, reserpine lost the ability to increase depolarization-induced FFN511 unloading after depletion of ready releasable pool with hyperosmotic sucrose. Cholesterol oxidase and sphingomyelinase modified atrial membranes, changing in opposite manner fluorescence of lipid ordering-sensitive probe. Plasmalemmal cholesterol oxidation increased FFN511 release upon K+-depolarization and more markedly potentiated FFN511 unloading in the presence of reserpine. Hydrolysis of plasmalemmal sphingomyelin profoundly enhanced the rate of FFN511 loss due to K+-depolarization, but completely prevented potentiating action of reserpine on FFN511 unloading. If cholesterol oxidase or sphingomyelinase got access to membranes of recycling synaptic vesicles, then the enzyme effects were suppressed. Hence, a fast neurotransmitter reuptake dependent on exocytosis of vesicles from ready releasable pool occurs during presynaptic activity. This reuptake can be enhanced or inhibited by plasmalemmal cholesterol oxidation or sphingomyelin hydrolysis, respectively. These modifications of plasmalemmal (but not vesicular) lipids increase the evoked neurotransmitter release.

Revisiting Alpha-Synuclein Pathways to Inflammation.

Alpha-synuclein (α-Syn) is a short presynaptic protein with an active role on synaptic vesicle traffic and the neurotransmitter release and reuptake cycle. The α-Syn pathology intertwines with the formation of Lewy Bodies (multiprotein intraneuronal aggregations), which, combined with inflammatory events, define various α-synucleinopathies, such as Parkinson's Disease (PD). In this review, we summarize the current knowledge on α-Syn mechanistic pathways to inflammation, as well as the eventual role of microbial dysbiosis on α-Syn. Furthermore, we explore the possible influence of inflammatory mitigation on α-Syn. In conclusion, and given the rising burden of neurodegenerative disorders, it is pressing to clarify the pathophysiological processes underlying α-synucleinopathies, in order to consider the mitigation of existing low-grade chronic inflammatory states as a potential pathway toward the management and prevention of such conditions, with the aim of starting to search for concrete clinical recommendations in this particular population.

Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches.

Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves: (1) resealing injured axons; (2) reconstructing the cytoskeletal structure inside axons; (3) re-establishing healthy growth cones; and (4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regeneration-reconnection after spinal cord injury.

GABA Release from Astrocytes in Health and Disease.

Astrocytes are the most abundant glial cells in the central nervous system (CNS) mediating a variety of homeostatic functions, such as spatial K+ buffering or neurotransmitter reuptake. In addition, astrocytes are capable of releasing several biologically active substances, including glutamate and GABA. Astrocyte-mediated GABA release has been a matter of debate because the expression level of the main GABA synthesizing enzyme glutamate decarboxylase is quite low in astrocytes, suggesting that low intracellular GABA concentration ([GABA]i) might be insufficient to support a non-vesicular GABA release. However, recent studies demonstrated that, at least in some regions of the CNS, [GABA]i in astrocytes might reach several millimoles both under physiological and especially pathophysiological conditions, thereby enabling GABA release from astrocytes via GABA-permeable anion channels and/or via GABA transporters operating in reverse mode. In this review, we summarize experimental data supporting both forms of GABA release from astrocytes in health and disease, paying special attention to possible feedback mechanisms that might govern the fine-tuning of astrocytic GABA release and, in turn, the tonic GABAA receptor-mediated inhibition in the CNS.

Leki przeciwdepresyne typu SNRI — medycyna oparta na faktach i doświadczeniu

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants are drugs registered for the treatment of depression and anxiety disorders. These drugs affect the reuptake of both serotonin and noradrenaline. There are two such drugs available in Poland: venlafaxine and duloxetine. The mechanism of venlafaxine’s antidepressant effect in humans is believed to be related to increased neurotransmitter activity in the central nervous system (CNS). Preclinical studies have shown that venlafaxine and its major metabolite (O-demethylenlafaxine, ODV) are serotonin and norepinephrine reuptake inhibitors. Venlafaxine is also a weak dopamine reuptake inhibitor. Venlafaxine acts by blocking neurotransmitter transport and reuptake proteins and acts through postsynaptic terminals, ultimately enhancing postsynaptic stimulation. Duloxetine is an inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake (e.g. in frontal regions), and has no significant affinity for histamine, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular serotonin and norepinephrine concentrations in different brain areas in animals. In this paper we will discuss the most important literature data concerning the above mentioned drugs, as well as define a patient profile that could most benefit from individually selected treatment.

TCA and SSRI Antidepressants Exert Selection Pressure for Efflux-Dependent Antibiotic Resistance Mechanisms in Escherichia coli.

Microbial diversity is reduced in the gut microbiota of animals and humans treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). The mechanisms driving the changes in microbial composition, while largely unknown, is critical to understand considering that the gut microbiota plays important roles in drug metabolism and brain function. Using Escherichia coli, we show that the SSRI fluoxetine and the TCA amitriptyline exert strong selection pressure for enhanced efflux activity of the AcrAB-TolC pump, a member of the resistance-nodulation-cell division (RND) superfamily of transporters. Sequencing spontaneous fluoxetine- and amitriptyline-resistant mutants revealed mutations in marR and lon, negative regulators of AcrAB-TolC expression. In line with the broad specificity of AcrAB-TolC pumps these mutants conferred resistance to several classes of antibiotics. We show that the converse also occurs, as spontaneous chloramphenicol-resistant mutants displayed cross-resistance to SSRIs and TCAs. Chemical-genomic screens identified deletions in marR and lon, confirming the results observed for the spontaneous resistant mutants. In addition, deletions in 35 genes with no known role in drug resistance were identified that conferred cross-resistance to antibiotics and several displayed enhanced efflux activities. These results indicate that combinations of specific antidepressants and antibiotics may have important effects when both are used simultaneously or successively as they can impose selection for common mechanisms of resistance. Our work suggests that selection for enhanced efflux activities is an important factor to consider in understanding the microbial diversity changes associated with antidepressant treatments. IMPORTANCE Antidepressants are prescribed broadly for psychiatric conditions to alter neuronal levels of synaptic neurotransmitters such as serotonin and norepinephrine. Two categories of antidepressants are selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs); both are among the most prescribed drugs in the United States. While it is well-established that antidepressants inhibit reuptake of neurotransmitters there is evidence that they also impact microbial diversity in the gastrointestinal tract. However, the mechanisms and therefore biological and clinical effects remain obscure. We demonstrate antidepressants may influence microbial diversity through strong selection for mutant bacteria with increased AcrAB-TolC activity, an efflux pump that removes antibiotics from cells. Furthermore, we identify a new group of genes that contribute to cross-resistance between antidepressants and antibiotics, several act by regulating efflux activity, underscoring overlapping mechanisms. Overall, this work provides new insights into bacterial responses to antidepressants important for understanding antidepressant treatment effects.

1,5-Dichloroethanoanthracene Derivatives As Antidepressant Maprotiline Analogs: Synthesis, DFT Computational Calculations, and Molecular Docking

The chlorinated tetracyclic 1,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-12-yl)-N-methylmethanamine 1, a maprotiline analog, has been synthesized via reduction and the Diels–Alder reaction followed by reductive amination of aldehyde 2.1D-NMR (DEPT) and 2D-NMR (HSQC, DQF-COSY) techniques were recruited for structural elucidation in addition to HRMS. Density functional theory calculations were performed to identify the possible isomers of the intermediate compound aldehyde 2; these calculations were in good agreement with experimental results where aldehyde 2 could exist in three isomers with comparable energies. In addition, the side chain of this aldehyde 2 was extended via the Wittig reaction to obtain the unsaturated ester 5 that was subjected to selective olefinic catalytic hydrogenation to obtain the corresponding saturated ester 6. Molecular docking simulation showed that all the compounds (1, 2, 5, and 6) have high antidepressant activities and form stable complexes with LeuT by inhibiting the neurotransmitter reuptake at the synapse and hence are good candidates as antidepressant drugs.