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Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is associated with amyloid-β (Aβ) accumulation that might be hindered by autophagy. There are two ways to induce autophagy: through mTOR-dependent and mTOR-independent pathways (here, by means of rapamycin and trehalose, respectively). The aim of this study was to evaluate the contribution of these pathways and their combination to the treatment of experimental AD. Mice were injected bilaterally intracerebroventricularly with an Aβ fragment (25-35) to set up an AD model. Treatment with rapamycin (10 mg/kg, every other day), trehalose consumption with drinking water (2 mg/mL, ad libitum), or their combination started 2 days after the surgery and lasted for 2 weeks. Open-field, plus-maze, and passive avoidance tests were used for behavioral phenotyping. Neuronal density, Aβ accumulation, and the expression of autophagy marker LC3-II and neuroinflammatory marker IBA1 were measured in the frontal cortex and hippocampus. mRNA levels of autophagy genes (Atg8, Becn1, and Park2) were assessed in the hippocampus. Trehalose but not rapamycin caused pronounced prolonged autophagy induction and transcriptional activation of autophagy genes. Both drugs effectively prevented Aβ deposition and microglia activation. Autophagy inhibitor 3-methyladenine significantly attenuated autophagy activation and disturbed the effect of the inducers on Aβ load. The inducers substantially reversed behavioral and neuronal deficits in Aβ-injected mice. In many cases, the best outcomes were achieved with the combined treatment. Thus, trehalose alone or combined autophagy activation by the two inducers may be a promising treatment approach to AD-like neurodegeneration. Some aspects of interaction between mTOR-dependent and mTOR-independent pathways of autophagy are discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Recent research has provided novel insights into the major depressive disorder (MDD) and identified certain biomarkers of this disease. There are four main mechanisms playing a key role in the related pathophysiology, namely (1) monoamine systems dysfunction, (2) stress response, (3) neuroinflammation, and (4) neurotrophic factors alteration. Robust evidence on the decreased homovanillic acid in the cerebrospinal fluid (CSF) of patients with MDD supports a rationale for therapeutic stimulation of the medial forebrain bundle activating the dopamine reward system. Both activation and suppression of the hypothalamic-pituitary-adrenal (HPA) axis in MDD and related conditions indicate usefulness of its evaluation for the disease subtyping. Elevated proinflammatory cytokines (specifically, interleukin-6) in CSF imply the role of neuroinflammation resulting in activation of the tryptophan-kynurenine pathway. Finally, neuroplasticity and trophic effects of the brain-derived neurotrophic factor (BDNF) may be related to both structural abnormalities of the brain in MDD and the underlying mechanisms of various therapies. In addition, the gut-brain interaction is pivotal, since lack of beneficial microbes confer the risk of MDD through negative effects on the dopamine system, HPA axis, and vagal nerve. All these factors may be highly relevant to treatment of MDD with contemporary brain stimulation therapies., Competing Interests: Conflict of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The neuroprotective effect of autophagy activation by rapamycin and trehalose was studied in a mouse model of Parkinson's disease (PD) induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both rapamycin (10 mg/kg/day, 7 days) and trehalose (2% in drinking water, 7 days) increased the expression of LC3-II (a marker of autophagy activation) in the frontal cortex and striatum of normal C57Bl/6J mice, with signs of an additive effect. Autophagy stimulation in the striatum was confirmed by a lysosomal osmotic test. In the model of MPTP-induced PD, the two drugs were applied starting from the 2nd day after subchronic daily MPTP administration (20 mg/kg/day, 4 days). A marked increase in LC3-II expression in the striatum was detected under the action of trehalose and in the S. nigra after combined treatment with rapamycin and trehalose. The drugs had a positive effect for recovery of dopaminergic neurons and neuroprotection after MPTP-induced PD-like injury. The therapeutic effect was proven by active restoration of tyrosine hydroxylase (TH) content in the striatum and S. nigra and by improved cognition measured by the passive avoidance learning task. The results revealed the additive effect of the combined treatment with rapamycin and trehalose on dopaminergic deficits (according to the levels of TH expression in the nigrostriatal system) but not on the behavioral performance in the mouse PD model. Thus, the autophagy activation through different pathways by the combination of rapamycin and trehalose reverses both neuronal dopaminergic and behavioral deficits in vivo and seems to be a promising therapy for PD-like pathology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

One of the important factors in aging is oxidative stress and aging-related disturbances are believed be ameliorated by antioxidants. Diosgenin is a bio-active ingredient of dioscorea that is widely used in Chinese medicine, shows anti-oxidant activity and improves some aging-related deficits in senescent and menopausal animals. We compared alterations in behavior, biochemical parameters (plasma levels of the uric acid, creatinine, calcium, phosphate, total cholesterol, low-density lipoprotein cholesterol and triglycerides, and the plasma activity of aminotransferases AST and ALT), and sperm motility in two models of accelerated senescence (d-galactose-induced (150 mg/kg/day, i.p., 57 days) aging in Wistar rats vs. genetically defined in OXYS rats) and examined the protective effects of diosgenin (10 or 50mg/kg/day, p.o., 57 days). Both models had augmented levels of ALT activity indicating hepatopathology. Compared to d-galactose-treated animals, OXYS rats demonstrated profound biochemical alterations (hypocalcemia, hypophosphatemia, and hypocholesterolemia) and behavioral deficits (impaired object recognition, decreased sexual motivation and locomotor activity, retarded learning) that confirmed the difference in the mechanisms of accelerated senescence in these models. We first showed diminished sperm motility in males of both models of accelerated senescence studied. Chronic diosgenin treatment failed to improve biochemical and behavioral disturbances and had some undesirable side effects on body weight and working memory in OXYS rats. However, diosgenin restored moderately decreased sperm motility in d-galactose-treated Wistar males and might be recommended for treatment of mild age-related reproductive dysfunctions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The study of the interaction between nervous and immune systems in the mechanism of psychopathology is an important problem of neuroscience. Catalepsy (freezing reaction) is a passive defensive strategy in response to threatening stimuli. An exaggerated form of catalepsy is a syndrome of some grave mental disorders. Both the brain serotonin (5-HT) and immune systems were shown to be involved in the mechanism of catalepsy. Here we compared the effects of two doses (50 or 200 μg/kg, ip) of innate immune system activator, bacterial lipopolysaccharide (LPS), on catalepsy, 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the hippocampus, striatum, and midbrain of mice of catalepsy-prone (CBA/Lac and AKR.CBA-D13Mit76) and catalepsy-resistant (AKR/J) strains. The expression of LPS-induced catalepsy as well as 5-HIAA/5-HT ratio in the midbrain and striatum were significantly higher in mice of the catalepsy-prone strains compared with animals of the catalepsy-resistant strains. These results indicated an involvement of the brain 5-HT system in the cataleptogenic effect of LPS and open up new vistas for understanding the nervous-immune mechanism of behavioral disorders., (© 2013.)

Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain. The 1473G allele of the C1473G polymorphism in mTPH2 gene is associated with reduced enzyme activity and serotonin synthesis rate in the mouse brain. Here, the influence of the 1473G allele on the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), citalopram (2.5 or 5.0mg/kg) and paroxetine (5.0 or 10.0mg/kg), in the forced swim test was studied using B6-1473G and B6-1473C congenic mouse lines with the 1473G (decreased TPH2 activity) or 1473C (normal TPH2 activity) alleles, respectively, transferred to the genome of C57BL/6 mouse strain. Paroxetine (5.0 or 10.0mg/kg) and citalopram (2.5 or 5.0mg/kg) decreased immobility time in B6-1473C mice, while both doses of paroxetine and 2.5mg/kg of citaloprame did not alter immobility time in B6-1473G mice. However, 5.0mg/kg of citalopram reduced immobility in B6-1473G mice. The results provided genetic evidence of moderate association between 1473G allele and reduced sensitivity to SSRIs in mice., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Hygienic self-grooming is a behavioral adaptation for removing litter particles and pathogenic agents from animal fur and skin. We studied contribution of brain serotonin system into mechanisms regulating hygienic behavior in intact mice and mice with LPS(lipopolysaccharide)-induced sickness. A spot of fluorescent dye was applied on the back of a mouse, and the decrease in its fluorescence served as an index of fur cleaning efficiency estimated using original classifier algorithm. Agonist of 5-HT(₁A) receptor (8-OH-DPAT) or 5-HT(₂A/₂C) receptor (DOI) attenuated fur cleaning at a dose of 1 mg/kg but not of 0.2 mg/kg. MAO-A inhibitor clorgyline decreased hygienic self-grooming at a dose of 10 but not of 5 mg/kg. SSRI paroxetine had no effect while fluoxetine diminished hygienic behavior at the higher dose used (20 mg/kg). Inhibitory effect of LPS treatment (50 μg/kg) on fur cleaning was not altered by administration of p-MPPI (5-HT(₁A) receptor antagonist, 1mg/kg) or DOI (1mg/kg) while 8-OH-DPAT (1 mg/kg) produced additive effect. The results suggest the involvement of 5-HT(₁A) and 5-HT(₂A/₂C) brain serotonin receptors and MAO-A in the inhibition of hygienic behavior in mice. However, LPS-induced depression of fur cleaning appeared to be mediated via different mechanisms and enhanced by 5-HT(₁A) receptor activation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Thyroid hormones (TH) were hypothesized to affect behavior via neurotransmission alterations. The present study was aimed to reveal effects of chronic TH deficit and excess on some types of adaptive behavior (catalepsy, acoustic startle reflex, open-field performance), sexual arousal and cerebral 5-HT2A serotonin receptors of adult Wistar rats. Administration of thyroxine synthesis inhibitor, propylthiouracil (PTU, 50 mg/l, 28 days), in drinking water produced substantial decrease in plasma thyroxine level and body weight gain, attenuated significantly acoustic startle reflex amplitude, sexual motivation and plasma testosterone surge in response to receptive female introduction, increased predisposition to catalepsy without considerable effects on open-field performance. L-thyroxine treatment (T4, 0.5 mg/l, 28 days) caused significant plasma thyroxine augmentation, somatic growth retardation and disturbances in sexual but not in other types of behavior studied. TH dysfunctions markedly increased number of DOI-induced wet dog shakes reflecting high functional activity of 5-HT2A receptors without any effect on cortical 5-HT2A receptor mRNA level. The involvement of cerebral 5-HT2A receptors alterations at posttranslational level in mechanisms of TH effects on sexual arousal was suggested. The data attract particular attention to undesirable effects of PTU and L-thyroxine treatment on behavior.