Prolonged or intensive stress results in emotional and cognitive deficits and is a major risk factor for psychiatric disorders such as depression. Since the molecular mechanisms of how biological adaptations to stress go awry remains elusive, pharmaceutical development targeting stress has not been established. In rodents, repeated stress alters functions of multiple brain areas including the medial prefrontal cortex (mPFC) that confers stress resilience, thereby causing depression, anxiety, and working memory deficit. The mesocortical dopaminergic pathway that regulates such stress-coping functions is attenuated with repetition of stress via prostaglandin (PG) E₂, a bioactive lipid derived from arachidonic acid, and its receptor EP1. Several findings suggest that microglia activated by repeated stress are involved in emotional and cognitive changes as a source of inflammation-related molecules such as PGE₂ and IL-1β. IL-1 signaling is critical not only for emotional changes but also for microglial activation induced by repeated stress. Furthermore, purinergic signaling via the P2X7 receptor that can trigger PGE₂ and IL-1β production in microglia has been implicated in the pro-depressive effect of repeated stress as well as depressive disorders. Collectively, inflammation-related molecules that link repeated stress to mPFC dysfunction are potential targets of pharmaceutical development for psychiatric disorders.

View full abstract

The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers are trying to elucidate the mechanisms that underlie the discriminative stimulus effects of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, the patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ketamine, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. However, the mechanisms of the discriminative stimulus effects of hallucinogenic drugs are not yet fully clear. This review will briefly focus on the recent findings regarding hallucinogenic/psychotomimetic drug–induced discriminative stimulus effects in animals. In summary, recent research has demonstrated that there are at least two plausible mechanisms that can explain the cue of the discriminative stimulus effects of hallucinogenic drugs; one is mediated mainly by 5-HT₂ receptors, and the other is mediated through sigma-1 (σ₁)-receptor chaperone regulated by endogenous hallucinogenic ligand.

View full abstract

About 80% of CKD (chronic kidney disease) patients are hypertensive, and kidney function and blood pressure are clearly related to both physiologic and pathologic conditions in a “vicious cycle”. In this pathologic scenario, there is a renin–angiotensin system (RAS) hyperactivity associated to progression of renal damage. Current guidelines indicate as the first choice of antihypertensive intervention, the pharmacologic blockade of the RAS. Nonetheless, both response to treatment and renal protection have considerable inter-individual variability. The main aims of this review are to describe the genetic characteristics of RAS components and to identify the possible pharmacogenetic implications for RAS-blocker drugs in the hypertension–CKD scenario. To date, RAS polymorphisms have not been consistently associated to antihypertensive response and studies focusing on CKD are scarce. Nonetheless, pharmacogenetic studies for the RAS-blocker drugs could still be further explored, especially with new generation tools and focusing not only on the antihypertensive response, but also on renal protection as well.

View full abstract

We have recently found that combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and mice and that estrogen replacement and chronic treatment with Ginkgo biloba extract EGb 761 suppress the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of placental extract on the memory impairment and neuromorphological change in OVX/stress-subjected mice. Female Slc:ICR strain mice were randomly divided into four groups: vehicle-treated OVX, porcine placental extract (120 and 2160 mg/kg)-treated OVX, and sham-operated control groups. Two weeks after surgical operation, OVX mice underwent restraint stress for 21 days (6 h/day), and all animals were then subjected to a contextual fear conditioning test followed by morphological examination by Nissl staining. Placental extract was orally administered once daily until the behavioral analysis was carried out. Chronic treatment with both doses of placental extract improved the OVX/stress-induced fear memory impairment and Nissl-positive cell loss of the hippocampal CA3 region, although it did not affect the loss of bone mineral density and increase in body weight after OVX. These results have important implications for the neuroprotective and cognition-enhancing effects of placental extract in postmenopausal women.

View full abstract

In this study, we investigated the effect of L-carnosine (CAR) on prooxidant–antioxidant balance in several tissues of rats exposed to chronic stress. Both cold and immobilization stresses were applied to rats at the same time. In the stress group, rats were placed in restraint cages and kept in a cold room (+4°C) for 1 h for 21 days (5 days a week). Rats were injected with CAR (250 mg/kg, i.p.) at 30 min before stress application. Malondialdehyde, diene conjugate, protein carbonyl and nitrotyrosine levels, nonenzymatic (glutathione, vitamin E, and vitamin C), and enzymatic (catalase, superoxide dismutase and glutathione peroxidase) antioxidants were determined in the liver, heart, and brain tissues. Chronic cold plus immobilization stress was observed to affect especially the prooxidant–antioxidant status in the brain tissue of rats. This is the first report showing the beneficial effects of CAR on oxidative stress in the brain in rats exposed to stress.

View full abstract

Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and motor dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 – 10 nmol) induced brain damage and motor dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause motor dysfunction. However, FeCl₂ (10 nmol) caused motor dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron-chelating agent, prevented SNP-induced brain damage and motor dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 – 10 nmol), a natural anti-oxidant substance, dose-dependently prevented motor dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and motor dysfunction induced by FeCl₂ toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion.

View full abstract

We previously reported that higher therapeutic effects were obtained in rheumatoid arthritis (RA) patients and RA model animals when the dosing-times of methotrexate and tacrolimus were chosen according to the 24-h rhythms of the inflammatory response. Mizoribine (MZR) is an immunosuppressive agent and is used against RA in the same manner as methotrexate and tacrolimus. In this study, we examined whether a dosing-time dependency of the therapeutic effect of MZR could be detected in collagen-induced arthritis (CIA) rats. To measure C-reactive protein (CRP) and tumor necrosis factor (TNF)-α levels, blood was collected from CIA rats at different times. MZR was administered at two different dosing-times based on these findings and its effects and toxicity were examined. CRP and TNF-α concentrations in blood showed significant 24-h rhythms. The exacerbation of arthritis and excessive increase in leukocytes in CIA rats were markedly lower in the group treated with MZR at the dark phase than those of the group treated with MZR at the light phase. These findings suggest that the therapeutic index of RA therapy may be improved by administering MZR at a time in the day when the inflammatory reaction begins to activate.

View full abstract

Endothelial dysfunction caused by oxidative stress plays a key role in atherogenesis. This study investigated whether the anti-diabetic drug miglitol, an α-glucosidase inhibitor, which is currently available in clinical practice, can prevent endothelial cell apoptosis and whether it might restore impaired vascular relaxation under oxidative stress. The bEnd.3 cells, a microvascular endothelial cell line, were pre-treated with various concentrations of miglitol and then were incubated with H₂O₂ for 1 – 2 h. Treatment of bEnd.3 cells with miglitol resulted in the protection of cell viability, suppression of mitochondrial superoxide production, and DNA strand breakage under the oxidative stress. These effects of miglitol were associated with the activation of AMP-activated protein kinase (AMPK) and the phosphorylation of endothelial nitric oxide synthase (eNOS). In aortic rings with endothelium, acetylcholine (Ach)-induced relaxation was attenuated by H₂O₂. We found that this impaired relaxation was restored by acute treatment with miglitol. Compound C, an AMPK inhibitor, inhibited the amelioration of vascular relaxations treated with miglitol. These results suggest that miglitol might protect against endothelial cells damage under oxidative stress via inhibition of endothelial cell apoptosis and mitochondrial superoxide production, which are mediated by the activation of AMPK and the phosphorylation of eNOS.

View full abstract

Measurement of neurotransmitters in the spinal dorsal horn in conscious animals remains a technical challenge. Here we applied concentric microdialysis to measure formalin-induced glutamate (Glu) release in the ipsilateral dorsal horn in conscious, freely-moving rats. Hind paw formalin injection induced flinching nociceptive behaviors accompanied by increased Glu in the dorsal horn (maximum = 294%). Both flinching and Glu increase were prevented by morphine (3 mg/kg, s.c.). Accordingly, concentric microdialysis is a sensitive technique for studying neurochemical modulation induced by pain and analgesics in the spinal dorsal horn of awake rats. Measurement of Glu provides information on modulation of excitatory signals.

View full abstract

Randomized clinical trials have shown that pramipexole has an antidepressant effect in patients with Parkinson’s disease. We investigated the comparative efficacy of pramipexole toward dopamine receptor D₂ and D₃ expression in rat brain. Groups of rats were treated subacutely with pramipexole (1 mg/kg), imipramine (10 mg/kg), or bromocriptine (5 mg/kg), with appropriate controls. Using real-time RT-PCR and immunoblotting, dopamine receptor D₂ and D₃ expression was up-regulated in the striatum following pramipexole treatment, while imipramine and bromocriptine had no significant effects. These findings support that pramipexole exerts additional therapeutic benefits such as decreasing depression by increasing dopamine receptor D₃ expression in the striatum.

View full abstract