CNS & Neurological Disorders - Drug Targets - Volume 14, Issue 3, 2015

Psychological stress leads to activation and proliferation of microglial cells in different brain regions. These effects are mediated by inflammatory cytokines, as well as stress hormones including glucocorticoids and norepinephrine. Eliminating microglia from the nervous system or blocking their activation prevented the stress-induced impairments on brain cognitive functions. We conclude that microglial cells are important meditators underlying anti-depression therapies.

A 41-year-old woman with Major Depressive Disorder-Recurrent was treated with topiramate at 150 mg/day. After this administration, she developed intense pruritus and skin lesions due to scratching. Consequently, she was weaned off topiramate and the lesions regressed. Pruritus and cutaneous lesions are extremely rare side effects of topiramate, so we report an interesting case of skin reaction to this drug.

Evidence has been accumulated showing that inflammatory and cell death pathways are altered both in brain and periphery during Parkinson disease (PD). Neuronal loss in PD is associated with chronic neuroinflammation characterized by microglia activation through the release of reactive oxygen radicals, cytokines, and Prostaglandin E2. The release of these inflammatory mediators in addition to deprivation in growth factors and increase of calcium and dopamine seem implicated in triggering apoptosis. The interaction of leucine-rich repeat kinase and Fas- Associated protein with Death Domain has been implicated in the switching-on of the extrinsic apoptotic pathway via caspase-8 activation, while deficiency in PTEN induced putative kinase 1 has been shown to cause Ca2+ accumulation in mitochondria, increased generation of reactive oxygen species and intrinsic cell death. Autophagy/mitophagy appears to be impaired in the brain during PD; this impairment could be related to defective degradation of mutant α-synuclein and consequent apoptotic cell death. Regarding the peripheral blood, reduced amounts of dopamine, reduced levels of immunoreactivity for tyrosine hydroxylase and dopamine active transporter, and alterations of dopamine receptor expression have been detected in mononuclear cells from PD patients. In addition, mononuclear cells from PD patients show mitochondrial, ubiquitin–proteasome system dysfunction and up-regulation of α-synuclein gene, associated to high expression of the Fas molecule, activation of caspase-3 and -9 and proneness to apoptosis. These and other observations reported in this mini-review suggest that a better understanding of molecular dysfunctions in inflammatory and cell death/autophagy pathways, both in the brain and peripheral blood, could provide useful targets for future investigation on drug-discovery and biomarker identification in PD.

Understanding the pathogenesis of non-iatrogenic comorbidities of schizophrenia may provide insights into the pathogenesis of schizophrenia itself. First-episode, drug-naïve schizophrenia patients are at high risk of thromboembolic events, diseases related to substance abuse, sexual dysfunction, reproductive disorders, inflammatory and autoimmune diseases, as well as complications of hyperinsulinemia or hyperhomocysteinemia. This review focuses on the role of reduced plasminogen activator activity in non-iatrogenic comorbidity of schizophrenia. By preventing thrombus dissolution, low tissue plasminogen activator activity increases the risk of thrombotic events. Components of the plasminogen activator system also play a key role in reproduction. Both illicit drugs and tobacco increase plasminogen activator levels in the central nervous system, which seems to relieve symptoms of the mental disorder. Chronic alcoholism, sexual dysfunction, inflammatory and autoimmune disorders, and complications of hyperinsulinemia or hyperhomocysteinemia are somehow related to low plasminogen activator activity. Plasminogen activator mediates several neurochemical processes that seem to prevent or reverse gray-matter atrophy seen in first-episode schizophrenia patients. Such processes include cleavage of brain-derived neurotrophic factor precursor to an anti-apoptotic neurotrophin and activation of N-methyl-D-aspartate receptor. Controlled, randomized studies are needed to determine if measures aimed at correcting plasminogen activator activity can improve the quality of life, reduce morbidity and mortality rates, and particularly improve the course of schizophrenia.

Compulsions, like pathological gambling, binge-eating disorder, alcohol, tobacco or cocaine abuse and compulsive shopping have similar neurophysiological processing. This study aimed to examine the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving patient control over compulsive behavior. The rTMS modulatory role in cortical mesolimbic pathways possibly implies improvement of the inhibitory control system and compulsive consumption drive. Thus, craving reduction would be a component for control achievement. Within this context, 17 studies were found. Most studies applied rTMS over the left dorsolateral prefrontal cortex. Craving reduction was observed in 10 studies and was associated with improved control of compulsion in two of them. In one study reduction in consumption was found without reduction in craving. In addition, improvement in decision making was found in one study.

Problematic Internet use is a worldwide social issue and it can be found in any age, social, educational, or economic range. In some countries like China and South Korea internet addiction (IA) is considered a public health condition and this governments support research, education and treatment. Internet addiction has been associated with others psychiatric disorders. Panic disorder (PD) and Obsessive Compulsive Disorder (OCD) are anxiety disorders that involve a lot of damages in patient’s life. We report a treatment of a patient with Panic Disorder and Obsessive Compulsive Disorder and internet addition involving pharmacotherapy and Cognitive Behavioral Therapy (CBT). The Cognitive Behavioral Therapy was conducted 1 time per week during 10 weeks and results suggest that the treatment was an effective treatment for the anxiety and for the internet addiction.

Background: Results of several studies suggest that serum amino acids monitoring in migraine might be useful as an objective measurement of the disease status. Objective: The aim of the present work was to analyze the profile of aliphatic and aromatic amino acids in blood serum of migraine patients without and with aura between attacks. Methods: A total number of 37 migraine patients (26 with migraine without aura and 11 with migraine with aura), mean age 39±12 years, and 40 age-matched healthy subjects as the control group, mean age 38±14 years, were included into the study. The levels of glutamic acid, glutamine, histidine (His), valine (Val), isoleucine, leucine (Leu), phenyloalanine, lysine were evaluated. Results: The level of His was significantly higher in both groups of migraine patients (without and with aura) compared to the control group (F(2,74)=10.17, p=0.00). The levels of Val and Leu were significantly different in migraine without but not with aura, when compared with the control group (F(2,74)=4.70, p=0.01 and F(2,74)=4.39, p=0.02, respectively). Conclusion: We found higher level of His in migraine patients without and with aura and lower level of Val and Leu in patients with migraine without aura.

Probenecid has been widely used in the treatment of gout, but evidence suggests that it may also have antinociceptive effects in different inflammatory and pain conditions. We examined the potential modulatory effects of probenecid on behavioural and morphological markers in the orofacial formalin test of the rat. One hour after pre-treatment with vehicle or probenecid (1 mmol/kg body weight) intraperitoneally, 50μl 1.5% formalin solution or physiological saline was injected subcutaneously into the right whisker pad of rats. The rubbing activity directed to the injected whisker pad was then measured for a period of 45 minutes. Four hours after formalin injection, the caudal part of spinal trigeminal nucleus was removed and subjected to c-Fos and neuronal nitric oxide synthase (nNOS) immunohistochemistry and to interleukin-1β and NAD(P)H:quinone oxidoreductase 1 (NQO1) Western blot. There was a significant decrease in formalin-induced biphasic behavioural response and c-Fos and nNOS immunoreactivity in the rats that were pre-treated with probenecid. However there were no alterations in expression of interleukin-1β or NQO1 after formalin administration. Our results suggest that probenecid has an anti-nociceptive effect in the trigeminal inflammatory pain model. This effect may be through influencing the release of prostaglandin E2 or desensitizing the transient receptor potential channel subtype A member 1 or the transient receptor potential channel subtype V member 2 or the effect may be through modulating kynurenic acid levels in the central nervous system. Thus, probenecid might be a potential candidate for the treatment of trigeminal activation related pain conditions.

Notoginsenoside R1 (NTR1) is the main active ingredient of the well-known traditional Chinese herbal medicine Panax notoginseng, the root of Panax notoginseng (Burk.) F. H. Chen. Studies demonstrated that NTR1 may have some neuronal protective effects. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by β -amyloid protein (Aβ) deposition, neurofibrillary tangle formation and neuronal loss. This study was designed to explore the protective effect of NTR1 on an APP/PS1 double-transgenic mouse model of AD and investigate the possible mechanism. The 3-month-old mice were fed with 5 mg/(kg•d), 25 mg/(kg•d) NTR1 or vehicle via oral gavage for 3 months and changes in behavior, neuropathology, and amyloid pathology were investigated. The mice with NTR1 treatment showed significant amelioration in the cognitive function and increased choline acetyl transferase expression, as compared to the vehicle treated mice. NTR1 treatment inhibited Aβ accumulation and increased insulin degrading enzyme expression in both APP/PS1 mice and N2a-APP695sw cells, suggesting that of NTR1 may exert its protective effects through the enhancement of the Aβ degradation. Furthermore, our data showed that the increased level of peroxisome proliferator-activated receptor γ (PPARγ) and the up-regulation of insulin degrading enzyme induced by NTR1 were inhibited by administration of GW9662 (a PPARγ antagonist), indicating that the effect of NTR1 was mediated, at least in part, by PPARγ. Thus, our findings provide the evidences that NTR1 has protective effect on AD mouse model and NTR1 may be a potential candidate for AD treatment.

An increasing number of studies have demonstrated that insulin-degrading enzyme (IDE) plays an essential role in both the degradation and its activity of β-amyloid (Aβ). Therefore, the regulation of IDE expression and/or modification of IDE-dependent actions are two emerging strategies for the treatment of Alzheimer’s disease (AD). We previously observed that geniposide, a novel agonist of glucagon-like peptide 1 receptor (GLP-1R), could attenuate Aβ-induced neurotoxicity by regulating the expression of IDE in primary cortical neurons. However, the signal transduction mechanisms underlying this effect were not elucidated. The present study, therefore examined and explored the cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002 (an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1 (inhibitor for c-Src), GW9662 (antagonist for peroxisome proliferator-activated receptor γ, PPARγ), H89 (an inhibitor for protein kinase A, PKA) and AG1478 (an antagonist for epidermal growth factor receptor, EGFR) prohibited the up-regulation of IDE induced by geniposide in primary cortical neurons. Further, geniposide also enhanced the phosphorylation of PPARγ and accelerated the release of phosphorylated FoxO1 (forkhead box O1) from nuclear fraction to the cytosol. Moreover, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE in neurons.

Drug resistance in epilepsy is considered as a complicated and multifactorial problem. Poor penetration of antiepileptic drugs (AEDs) across blood-brain barrier (BBB) into the brain, which results in insufficient level of the drugs at the targeted brain region, has been discussed as one mechanism contributing to pharmacoresistance of epilepsies. Therefore, modulating permeability of BBB is the effective treatment strategy since it facilitates the entry of AEDs into the central nervous system (CNS). Recently, signaling through receptors for the adenosine has been identified as a potent modulator of BBB permeability. This paper aimed to investigate the effects of auxiliary application of adenosine receptor (AR) agonist on amygdala-kindled seizures in adult male Wistar rats. When fully kindled seizures were achieved by daily electrical stimulation of the amygdala, rats were randomly divided into three groups: control, phenytoin, and phenytoin (PHT) + 5&apos-N-ethylcarboxamidoadenosine (NECA) groups. NECA (0.08mg/kg, i.v.) was applied to the PHT+NECA group after the administration of PHT (75mg/kg, i.p. on the first day; 50mg/kg, i.p. on the following 9 days). Intravenous infusion of NECA resulted in a significant increase in brain PHT levels as compared with the PHT treatment alone. On the other hand, the auxiliary application of NECA dramatically decreased the frequency of generalized seizures and seizure stage, shortened duration of afterdischarge and generalized seizures, as well as the elevated the afterdischarge threshold and generalized seizures threshold. Our study demonstrated that auxiliary application of AR agonist enhanced brain antiepileptic drug levels and strengthened the anticonvulsant properties of PHT against amygdala kindled seizures.

We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38°C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4-to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x106) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future.

Transient, global cerebral ischemia (TGCI) causes hippocampal/cortical damage and the persistent loss of welltrained, long-term memory (retrograde amnesia). Fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids, abolishes such amnesia in the absence of neurohistological protection. The present study investigated whether FO prevents ischemia-induced oxidative stress and whether such an action contributes to the lasting effect of FO on memory recovery. In a first experiment, FO was administered for 4 days prior to ischemia, and antioxidant status was subsequently measured after 24 h of reperfusion. In another experiment, naive rats were trained in an eight-arm radial maze until they achieved asymptotic performance and then subjected to TGCI. One group of rats received FO as in the first experiment (i.e., 4 days prior to ischemia), whereas another group received FO for 4 days prior to ischemia plus 6 days postischemia. Retrograde memory performance was assessed 2-5 weeks after ischemia. TGCI depleted the level of antioxidant enzymes and increased the amount of protein carbonylation, indicating oxidative damage. Fish oil reversed oxidative damage to control levels. The same treatment that attenuated oxidative stress after 24 h of reperfusion also prevented retrograde amnesia assessed several weeks later. This antiamnesic effect afforded by short preischemia treatment was comparable to 10 days of treatment but not as consistent. These data indicate that an antioxidant action in the hyperacute phase of ischemia/reperfusion may contribute to the long-term, antiamnesic effect of FO.

Acori graminei Rhizoma (AGR), the dry rhizoma of Acorus gramineus Soland (Araceae), has been used as an Asian traditional herbal medicine against senile dementia, stroke, and cardiovascular disease. Previous studies have revealed neuroprotective effects of AGR on neuronal damage and learning impairment, while mostly focused on the effect of volatile oil fraction of AGR. This study aimed to investigate the neuroprotective effects of different extract fractions from AGR against Alzheimer disease-like symptoms induced by Amyloid Beta (Aß) 1-42 intra-hippocampal injection. On day 7 after intra-hippocampal injection of saline or Aβ1-42, spatial memory was assessed by the first Morris water maze, followed by 3-week intra-gastric administration of saline or water extract, volatile oil fraction, or defatted decoction fraction of AGR respectively. Mice were subsequently subjected to the second Morris water maze task. Levels of Aβ1-42 and expressions of doublecortin and nestin in the hippocampus were examined using immunohistochemistry. Our results suggested that treatment with these different extract fractions from AGR could ameliorate cognitive impairment and down-regulate expressions of doublecortin and nestin in the hippocampus of Aβ1-42 injected mice, in which water extract and volatile oil fractions were more effective in spatial memory than defatted decoction fraction.

Cholinergic precursors increasing choline availability and acetylcholine synthesis/release may represent a therapeutic approach for countering cognitive impairment occurring in adult-onset dementia disorders. Choline alphoscerate (alpha-gliceryl-phosphoryl-choline, GPC) is among cholinergic precursors the most effective in enhancing acetylcholine biosynthesis and release in animal models. This study was designed to assess if a long-term treatment with GPC modify cerebrovascular components [perivascular astrocytes, blood-brain barrier (BBB) and microvessels] and endothelial inflammatory markers expression in spontaneously hypertensive rats (SHR) used as a model of brain vascular injury. Male SHR aged 32 weeks and age-matched normotensive Wistar-Kyoto rats were treated for 4 weeks with GPC (150 mg/kg/day) or a vehicle. Intracerebral arteries of different brain areas, perivascular astrocytes, BBB and endothelial inflammatory markers were assessed by quantitative morphological and immunohistochemical techniques. No significant changes in the size of perivascular astrocytes were observed in SHR versus normotensive Wistar-Kyoto rats, whereas the expression of the BBB marker aquaporin-4 increased in SHR. This phenomenon was countered by GPC treatment. On the contrary, GPC has no vasodilator effect on brain micro-vessels. Endothelial markers and vascular adhesion molecules expression were not homogeneously affected by hypertension and GPC treatment in intracerebral vessels. The observation that treatment with GPC reversed BBB changes and countered to some extent micro-vessels changes occurring in SHR could explain data of clinical trials reporting an improvement of cognitive function in subjects suffering from cerebrovascular disorders and treated with GPC. These preclinical data suggest that the compound could have a cerebrovascular protective effect deserving a further characterization.