Peng-Fei Wu

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.

Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury

AbstractMore and more attention in the field of drug discovery has been focused on the neuroprotection of natural compounds from traditional medicinal herbs. Cerebral ischemia is a complex pathological process involving a series of mechanisms, and a framework for the development of neuroprotectants from traditional herb medicine is a promising treatment for cerebral ischemia. Natural compounds with the effects of anti-oxidation, anti-inflammation, calcium antagonization, anti-apoptosis, and neurofunctional regulation exhibit preventive or therapeutic effects on experimental ischemic brain injury. According to the pharmacological mechanisms underlying neuroprotection, we evaluated natural products from traditional medicinal herbs that exhibit protective effects on ischemic brain injury and characterized the promising targets.

The cytotoxic mechanism of malondialdehyde and protective effect of carnosine via protein cross-linking/mitochondrial dysfunction/reactive oxygen species/MAPK pathway in neurons

The accumulation of malondialdehyde (MDA), a lipid peroxidation by-product that has been used as an indicator of cellular oxidation status, is significantly increased in many neurological diseases such as brain ischemia/reperfusion, Alzheimers disease and Parkinsons disease in vivo. In the present study, we found that MDA treatment in vitro reduced cortical neuronal viability in a time- and dose-dependent manner and induced cellular apoptosis as well as necrosis simultaneously. Furthermore, exposure to MDA led to accumulation of intracellular reactive oxygen species, dysfunction of mitochondria (denoted by the loss of mitochondrial transmembrane potential (Δψm)) and activation of JNK and ERK. Carnosine exhibited better protection against MDA-induced cell injury than antioxidant N-acetyl-cysteine (NAC) with its multi-potency, which alleviated MDA-induced protein cross-linking, Δψm decrease, reactive oxygen species burst, JNK and ERK activation. In conclusion, our results suggest that MDA induced cell injury in vitro via protein cross-linking and successive mitochondrial dysfunction, and the activation of reactive oxygen species-dependent MAPK signaling pathway. Carnosine alleviated all these alterations induced by MDA, but NAC merely inhibited Bcl-2 family-related activation of JNK and ERK. These results prompt the possibility that carnosine, but not other conventional antioxidants, can protect neurons against MDA-induced injury through decomposition of protein cross-linking toxicity and may serve as a novel agent in the treatment of neurodegenerative diseases.

Acid-Sensing Ion Channels Contribute to the Effect of Acidosis on the Function of Dendritic Cells

As an H+-gated subgroup of the degenerin/epithelial Na+ channel family, acid-sensing ion channels (ASICs) were reported to be involved in various physiological and pathological processes in neurons. However, little is known about the role of ASICs in the function of dendritic cells (DCs). In this study, we investigated the expression of ASICs in mouse bone marrow-derived DCs and their possible role in the function of DCs. We found that ASIC1, ASIC2, and ASIC3 are expressed in DCs at the mRNA and protein levels, and extracellular acid can evoke ASIC-like currents in DCs. We also demonstrated that acidosis upregulated the expression of CD11c, MHC class II, CD80, and CD86 and enhanced the Ag-presenting ability of DCs via ASICs. Moreover, the effect of acidosis on DCs can be abolished by the nonsteroidal anti-inflammatory drugs ibuprofen and diclofenac. These results suggest that ASICs are involved in the acidosis-mediated effect on DC function.

Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function

Deficits in learning and memory accompanied by age‐related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N‐methyl‐d‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP) in CA1 areas of hippocampal slices. Our results demonstrated that the impaired LTP induced by aging could be reversed by acute administration of reductants that can regulate thiol redox status directly, such as dithiothreitol or β‐mercaptoethanol, but not by classical anti‐oxidants such as vitamin C or trolox. This repair was mediated by the recruitment of aging‐related deficits in NMDAR function induced by these reductants and was mimicked by glutathione, which can restore the age‐associated alterations in endogenous thiol redox status. Moreover, antioxidant prevented but failed to reverse H2O2‐induced impairment of NMDAR‐mediated synaptic plasticity. These results indicate that the restoring of thiol redox status may be a more effective strategy than the scavenging of oxidants in the treatment of pre‐existing oxidative injury in learning and memory.

Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels

BACKGROUND AND PURPOSE Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen‐glucose deprivation‐reperfusion (OGD‐R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism.

Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly(ADP-Ribose) Polymerase-1 Inhibitors

A series of novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors were designed within 2-aminothiazole analogues (4-10) based on a constructed three-dimensional pharmacophore model. After synthesis, the inhibitory effect on PARP-1 activity and the cytoprotective action of these compounds were tested and evaluated. Among them, compounds 4-6 and 10 appeared to be potent PARP-1 inhibitors with IC(50) values less than 1 microM, which had been perfectly predicted by pharmacophore model. These compounds proved to be highly potent against cell injury induced by H(2)O(2) and oxygen-glucose deprivation (OGD) in PC12 cells. These novel 2-aminothiazole analogues are potentially applicable as neuroprotective agents for the treatment of neurological diseases.

Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases.

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases.

Orexin-A Activates Hypothalamic AMP-Activated Protein Kinase Signaling through a Ca2+-Dependent Mechanism Involving Voltage-Gated L-Type Calcium Channel

Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca2+ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor–phospholipase C–protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A’s orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A–induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca2+-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.

Aggravation of Seizure‐like Events by Hydrogen Sulfide: Involvement of Multiple Targets that Control Neuronal Excitability

Epileptic seizures are well‐known neurological complications following stroke, occurring in 3% of patients. However, the intrinsic correlation of seizures with stroke remains largely unknown. Hydrogen sulfide (H2S) is a gas transmitter that may mediate cerebral ischemic injury. But the role of H2S in seizures has not been understood yet. We examined the effect of H2S on seizure‐like events (SLEs) and underlying mechanisms.