Therapeutics of Alzheimer's disease: Past, present and future.

Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease

Stroke is one of the leading causes of death and disability worldwide, and ischemic stroke accounts for approximately 87% of cases. Improving post-stroke recovery is a major challenge in stroke treatment. Accumulated evidence indicates that the apelinergic system, consisting of apelin and apelin receptor (APLNR), is temporally dysregulated in ischemic stroke. Moreover, the apelinergic system plays a pivotal role in post-stroke recovery by inhibiting neuronal apoptosis and facilitating angiogenesis through various molecular pathways. In this review article, we summarize the temporal expression of apelin and APLNR in ischemic stroke and the mechanisms of their dysregulation. In addition, the protective role of the apelinergic system in ischemic stroke and the underlying mechanisms of its protective effects are discussed. Furthermore, critical issues in activating the apelinergic system as a potential therapy will also be discussed. The aim of this review article is to shed light on exploiting the activation of the apelinergic system to treat ischemic stroke.

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Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential.

Silent information regulator 1 (SIRT1), a type of histone deacetylase, is a highly effective therapeutic target for protection against ischemia reperfusion (IR) injury (IRI). Previous studies showed that melatonin preserves SIRT1 expression in neuronal cells of newborn rats after hypoxia-ischemia. However, the definite role of SIRT1 in the protective effect of melatonin against cerebral IRI in adult has not been explored. In this study, the brain of adult mice was subjected to IRI. Prior to this procedure, the mice were given intraperitoneal with or without the SIRT1 inhibitor, EX527. Melatonin conferred a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema, and increased neurological scores. The melatonin-induced upregulation of SIRT1 was also associated with an increase in the anti-apoptotic factor, Bcl2, and a reduction in the pro-apoptotic factor Bax. Moreover, melatonin resulted in a well-preserved mitochondrial membrane potential, mitochondrial Complex I activity, and mitochondrial cytochrome c level while it reduced cytosolic cytochrome c level. However, the melatonin-elevated mitochondrial function was reversed by EX527 treatment. In summary, our results demonstrate that melatonin treatment attenuates cerebral IRI by reducing IR-induced mitochondrial dysfunction through the activation of SIRT1 signaling.

Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice

It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants (i.e., cocaine, nicotine, and amphetamine) and alcohol may enhance hippocampal function and, therefore, the formation of augmented drug-context associations that contribute to the development of addiction. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawal-induced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates.

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Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’ disease

It is widely accepted that environmental stress is a risk factor for mental disorders. Glucocorticoid hormones play a vital role in the regulation of physiological response to stress. High concentrations of corticosterone can induce cellular damage in PC12 cells, which possess typical neuronal features. Apelin and its receptor APJ are widely distributed in the central nervous system including limbic structures involved in stress responses. Previous studies have suggested that apelin has a neuroprotective function. However, the effect of apelin on corticosterone-induced neuronal damage remains to be elucidated. In the present study, we explored the potential protective activity of apelin-13 in PC12 cells treated with corticosterone and its underling mechanisms. The viability of the cells, the apoptosis of the cells, the level of phosphorylation of Akt (p-Akt) and extracellular signal-regulated kinases (p-ERKs) and cleaved caspase-3 expression were detected by MTT, Hoechst staining and flow cytometer assays and Western blotting. Results showed that corticosterone induced cells viability loss, cell apoptosis, down-regulation of p-Akt and p-ERKs and up-regulation of cleaved caspase-3. The effects induced by corticosterone were attenuated by apelin-13 pretreatment. Furthermore, apelin-13-mediated anti-viability loss, antiapoptosis and caspase-3 suppression activities were blocked by specific inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY294002) and ERKs (PD98059). The data suggest that apelin-13 protects PC12 cells from corticosterone-induced apoptosis through activating PI3K/Akt and ERKs signaling pathways.

Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation.

Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer’s disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear. The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. Rats were exposed randomly to chronic mild stressors for 7 weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50 mg/kg) was administered daily during the last 2 weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus. We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine. Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits.

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats

Nicotine enhances contextual fear memory reconsolidation in rats.

To investigate the effects of the sensitizer rosiglitazone on the proliferation of vascular smooth muscle cell (VSMC) induced by high glucose administration. VSMCs were isolated from rat thoracic aortas and cultured in 10% fetal bovine serum (FBS). VSMC proliferation was evaluated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and cell counting. The cell cycle was examined by flow cytometry. The protein expressions of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases-2 (MMP-2) were evaluated by Western blotting. MMP-2 mRNA expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and gelatinolytic activity was determined by zymography. Promoted VSMC proliferation significantly increased the number of VSMCs in the S phase, the expressions of PCNA and MMP-2, and MMP-2 activity, as well as decreased the proportion of VSMCs in the G0/G1 phase. Rosiglitazone at a concentration of 10 μmol/L markedly inhibited glucose-induced VSMC proliferation (1.869 ± 0.22 vs 0.820 ± 0.15, P < 0.01). Concomitantly, rosiglitazone inhibited PCNA expression (0.96 ± 0.07 vs 0.75 ± 0.06, P < 0.05) and cell cycle progression from G0/G1 to S phase (the proportion of VSMCs in the G0/G1 and S phase were 69.6 ± 3.96% vs 84.3 ± 1.73% and 25.2 ± 1.73% vs 10.1 ± 1.42% (P < 0.01), respectively). Furthermore, rosiglitazone significantly decreased MMP-2 mRNA expression (0.98 ± 0.08 vs 0.71 ± 0.05, P < 0.05), protein expression (0.80 ± 0.04 vs 0.64 ± 0.03, P < 0.05) and MMP-2 activity (320 ± 25% vs 248 ± 21%, P < 0.05). Rosiglitazone significantly inhibited VSMC proliferation, at least in part by inhibiting high glucose-induced G1→S phase transition, PCNA expression and MMP-2 synthesis.

Shouhong Zhou

Papers

A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’ disease

Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation.

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats

Nicotine enhances contextual fear memory reconsolidation in rats.

Effects of rosiglitazone on the proliferation of vascular smooth muscle cell induced by high glucose.