Preventive and Therapeutic Potential of Vitamin C in Mental Disorders

In this review,we summarize the involvement of vitamin C in mental disorders by presenting available evidence on its pharmacological effects in animal models as well as in clinical studies.Vitamin C,especially its reduced form,has gained interest for its multiple functions in various tissues and organs,including central nervous system（CNS）.Vitamin C protects the neuron against oxidative stress,alleviates inflammation,regulates the neurotransmission,affects neuronal development and controls epigenetic function.All of these processes are closely associated with psychopathology.In the past few decades,scientists have revealed that the deficiency of vitamin C may lead to motor deficit,cognitive impairment and aberrant behaviors,whereas supplement of vitamin C has a potential preventive and therapeutic effect on mental illness,such as major depressive disorder（MDD）,schizophrenia,anxiety and Alzheimer＇s disease（AD）.Although several studies support a possible role of vitamin C against mental disorders,more researches are essential to accelerate the knowledge and investigate the mechanism in this field.

Identification and Function of Acid-sensing Ion Channels in RAW 264.7 Macrophage Cells

Activation of acid-sensing ion channels （ASICs） plays an important role in neuroinflammation. Macrophage recruitment to the sites of inflammation is an essential step in host defense. ASIC1 and ASIC3 have been reported to mediate the endocytosis and maturation of bone marrow derived macrophages. However, the expression and inflammation-related functions of ASICs in RAW 264.7 cells, another common macrophage, are still elusive. In the present study, we first demonstrated the presence of ASIC 1, ASIC2a and ASIC3 in RAW 264.7 macrophage cell line by using reverse transcriptase polymerase chain reaction （RT-PCR）, Western blotting and immunofluorescence experiments. The non-specific ASICs inhibitor amiloride and specific homomeric ASICla blocker PcTxl reduced the production of iNOS and COX-2 by LPS-induced activating RAW 264.7 cells. Furthermore, not only amiloride but also PcTxl inhibited the migration and LPS-induced apoptosis of RAW 264.7 cells. Taken together, our findings suggest that ASICs promote the inflammatory response and apoptosis of RAW 264.7 cells, and ASICs may serve as a potential novel target for immunological disease therapy.

Dimethyl sulfide,a metabolite of the marine microorganism,protects SH-SY5Y cells against 6-hydroxydopamine and MPP~＋-induced apoptosis

Dimethyl sulfide(DMS)has been historically recognized as a metabolite of the marine microorganism or a disgusting component for the smell of halitosis patients.In our recent study,DMS has been identified as a cytoprotectant that protects against oxidative-stress induced cell death and aging.We found that at near-physiological concentrations,DMS reduced reactive oxygen species(ROS)in cultured PC12 cells and alleviated oxidative stress.The radical-scavenging capacity of DMS at near-physiological concentration was equivalent to endogenous methionine(Met)-centered antioxidant defense.Methionine sulfoxidereductase A(MsrA),the key antioxidant enzyme in Met-centered defense,bound to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72,Tyr103,Glu115,followed by the release of dimethyl sulfoxide(DMSO).MTT assay and trypan blue test indicated that supplement of DMS exhibited cytoprotection against 6-hydroxydopamine and MPP+induced cell apoptosis.Furthermore,Msr A knockdown abolished the cytoprotective effect of DMS at near-physiological concentrations.The present study reveals new insight into the potential therapeutic value of DMS in Parkinson disease.

Modulation of long-term potentiation in the hippocampus by pharmacological approach:A novel strategy for the development of cognitive enhancers

Learning and memory not only provide the foundations of cognition, but are also closely related to sensory and motor function. Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are accompanied by deficits in synaptic function and cognition to varying degrees. The discovery of long-term potentiation (LTP) of hippocampal synaptic transmission, which has been recognized as a classical model of learning and memory at the cellular level, has spurred substantial progress in the development of cognitive enhancers in the past 20 years. Following intensive investigations into LTP, a variety of compounds and biologically active substances have been found to modulate hippocampal LTP via numerous molecular mechanisms including regulating presynaptic neurotransmitter release, postsynaptic N-methyl D-aspartate (NMDA) receptor activity, postsynaptic signal transduction and gene transcription. This review focuses on the progress of investigations into the overarching mechanisms of LTP, the drugs modulating LTP and prospects for the development of new drugs for treating cognitive impairments in the future.

Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder

Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-D-aspartate receptor(NMDAR). Age-related cognitive disorders includes Alzheimer’s disease(AD), vascular dementia(VD), and age-associated memory impairment(AAMI). Based on the critical role of NMDAR-dependent long-term potentiation(LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is Hydrogen sulfidemore similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.

S-palmitoylation regulates AMPA receptors trafficking and function: a novel insight into synaptic regulation and therapeutics

Glutamate acting on AMPA-type ionotropic glutamate receptor(AMPAR) mediates the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPAR by post-translational modifications is one of the key elements that allow the nervous system to adapt to environment stimulations. S-palmitoylation, an important lipid modification by post-translational addition of a long-chain fatty acid to a cysteine residue, regulates AMPA receptor trafficking, which dynamically affects multiple fundamental brain functions, such as learning and memory. In vivo, S-palmitoylation is controlled by palmitoyl acyl transferases and palmitoyl thioesterases.In this review, we highlight advances in the mechanisms for dynamic AMPA receptors palmitoylation,and discuss how palmitoylation affects AMPA receptors function at synapses in recent years.Pharmacological regulation of S-palmitoylation may serve as a novel therapeutic strategy for neurobiological diseases.

Rho-Associated Kinase Inhibitors Promote Microglial Uptake Via the ERK Signaling Pathway

Microglia are immunocompetent cells in the cen- tral nervous system that take up tissue debris and pathogens. Rho-associated kinase （ROCK） has been identified as an important regulator of uptake, proliferation, secretion, and differentiation in a number of cell types. Although ROCK plays critical roles in the microglial secretion of inflammatory factors, naigration, and morphology, its effects on microglial uptake activity have not been well characterized. In the present study, we found that treatment of BV2 microglia and primary microglia with the ROCK inhibitors Y27632 and fasudil increased uptake activity and was associated with morpholog- ical changes. Furthermore, western blots showed that this increase in uptake activity was mediated through the extracel- lular-signal-regulated kinase （ERK） signaling cascade, indi- cating the importance of ROCK in regulating microglial uptake activity.