Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model.

The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis.

Inflammation as a Mechanism of Bipolar Disorder Neuroprogression.

Bipolar disorder (BD) is a severe, debilitating psychiatric condition with onset in adolescence or young adulthood and often follows a relapsing and remitting course throughout life. The concept of neuroprogression in BD refers to the progressive path with an identifiable trajectory that takes place with recurrent mood episodes, which eventually leads to cognitive, functional, and clinical deterioration in the course of BD. Understanding the biological basis of neuroprogression helps to explain the subset of BD patients who experience worsening of their disorder over time. Additionally, the study of the neurobiological mechanisms underpinning neuroprogression will help BD staging based on systems biology. Replicated epidemiological studies have suggested inflammatory mechanisms as primary contributors to the neuroprogression of mood disorders. It is known that dysregulated inflammatory/immune pathways are often associated with BD pathophysiology. Hence, in this chapter, we focus on the evidence for the involvement of inflammation and immune regulated pathways in the neurobiological consequences of BD neuroprogression. Herein we put forth the evidence of immune markers from autoimmune disorders, chronic infections, and gut-brain axis that lead to BD neuroprogression. Further, we highlighted the peripheral and central inflammatory components measured along with BD progression.

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines.

Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.

Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats.

Evidence suggest that prenatal immune system disturbance contributes largely to the pathophysiology of neuropsychiatric disorders. We investigated if maternal immune activation (MIA) could induce inflammatory alterations in fetal brain and pregnant rats. Adult rats subjected to MIA also were investigated to evaluate if ketamine potentiates the effects of infection. On gestational day 15, Wistar pregnant rats received lipopolysaccharide (LPS) to induce MIA. After 6, 12 and 24 h, fetus brain, placenta, and amniotic fluid were collected to evaluate early effects of LPS. MIA increased oxidative stress and expression of metalloproteinase in the amniotic fluid and fetal brain. The blood brain barrier (BBB) integrity in the hippocampus and cortex as well integrity of placental barrier (PB) in the placenta and fetus brain were dysregulated after LPS induction. We observed elevated pro- and anti-inflammatory cytokines after LPS in fetal brain. Other group of rats from postnatal day (PND) 54 after LPS received injection of ketamine at the doses of 5, 15, and 25 mg/kg. On PND 60 rats were subjected to the memories tests, spontaneous locomotor activity, and pre-pulse inhibition test (PPI). Rats that receive MIA plus ketamine had memory impairment and a deficit in the PPI. Neurotrophins were increased in the hippocampus and reduced in the prefrontal cortex in the LPS plus ketamine group. MIA induced oxidative stress and inflammatory changes that could be, at least in part, related to the dysfunction in the BBB and PB permeability of pregnant rats and offspring. Besides, this also generates behavioral deficits in the rat adulthood's that are potentiated by ketamine.

A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients.

Bipolar disorder (BD) is a neuropsychiatric disorder that is characterized by a phasic course of affective episodes interspersed with a euthymic state. Epidemiological, clinical, genetic, post-mortem and preclinical studies have shown that inflammatory reactions and immune modulation play a pivotal role in the pathophysiology of BD. It is conceptualized that biomarkers of inflammation and immune responses should be employed to monitor the disease process in bipolar patients. The objective of this systematic review is to analyse the inflammatory markers involved in human studies and to explore each individual marker for its potential clinical application and summarize evidence regarding their role in BD. A systematic review of human studies to measure inflammatory markers was conducted, and the studies were identified by searching PubMed/MEDLINE, PsycINFO, EMBASE, and Web of Science databases for peer-reviewed journals that were published until September 2015. In this review, we included peripheral markers, genetic, post-mortem and cell studies with inflammatory biomarker analysis in BD. One hundred and two (102) papers met the inclusion criteria. The pro-inflammatory cytokines were elevated and the anti-inflammatory cytokines were reduced in BD patients, particularly during manic and depressive phases when compared to the controls. These changes tend to disappear in euthymia, indicating that inflammation may be associated with acute phases of BD. Even though there are promising findings in this field, further clinical studies using more established detection techniques are needed to clearly show the benefit of using inflammatory markers in the diagnosis, follow-up and prognosis of patients with BD.

Antioxidant Formulae, Shengmai San, and LingGuiZhuGanTang, Prevent MPTP Induced Brain Dysfunction and Oxidative Damage in Mice.

The present study was designed to evaluate the preventive effect of antioxidative traditional oriental medicine formulae, Shengmai San (SMS) and LingGuiZhuGanTang (LGZGT), against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (i.p 30 mg·kg(-1) for 5 consecutive days) induced neurotoxicity. In in vitro antioxidant assays measured with Trolox and butyl hydroxyl toluene as reference antioxidant revealed that SMS has higher scavenging potential against hydroxyl radical than superoxide anion radical, but LGZGT was the reverse. The neuroprotective effect of SMS and LGZGT against MPTP was evaluated in mice by behavioral, biochemical, and immunohistochemical studies. In the behavioral study, both SMS and LGZGT significantly reversed the locomotive impairment induced by MPTP. Simultaneously, both formulae significantly prevented the MPTP induced dopaminergic neuron loss assessed by tyrosine hydroxylase in the midbrain. Both SMS and LGZGT significantly attenuated the elevated lipid peroxidation and protein carbonyls levels by MPTP. The DNA damage induced by MPTP was also prevented by both formulae. Although a little difference in the protective functions was observed between the two formulae, such as in DNA damage and behavioral studies, the results indicate that both SMS and LGZGT with antioxidant property act as a good candidate applicable for the antioxidant based complementary therapies of neurodegenerative diseases.

Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom.

The present study was aimed to investigate the cognitive enhancing and anti-oxidant activities of Inonotus obliquus (Chaga) against scopolamine-induced experimental amnesia. Methanolic extract of Chaga (MEC) at 50 and 100 mg kg (-1)doses were administered orally for 7 days to amnesic mice. Learning and memory was assessed by passive avoidance task (PAT) and Morris water maze (MWM) test. Tacrine (THA, 10 mg kg (-1), orally (p.o)) used as a reference drug. To elucidate the mechanism of the cognitive enhancing activity of MEC, the activities of acetylcholinesterase (AChE), anti-oxidant enzymes, the levels of acetylcholine (ACh) and nitrite of mice brain homogenates were evaluated. MEC treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms. Further, MEC significantly reduced the oxidative-nitritive stress, as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner. In addition, MEC treatment significantly decreased the AChE activity in both the salt and detergent-soluble fraction of brain homogenates. Further, treatment with MEC restored the levels of ACh as did THA. Thus, the significant cognitive enhancement observed in mice after MEC administration is closely related to higher brain anti-oxidant properties and inhibition of AChE activity. These findings stress the critical impact of Chaga, a medicinal mushroom, on the higher brain functions like learning and memory.

Ocimum sanctum Linn. leaf extracts inhibit acetylcholinesterase and improve cognition in rats with experimentally induced dementia.

Cognitive disorders such as dementia, attention deficits, and Alzheimer's disease (AD) have been well investigated. However, effective interventions for the promotion and progression of AD are unavailable to date. The present work was undertaken to investigate the effects of the aqueous (300 and 500 mg/kg) and alcoholic (300 and 500 mg/kg) extracts of Ocimum sanctum Linn. leaves as an antidementic and anticholinesterase agent and also as an immunostimulant in rats. Maximal electroshock, atropine, and cyclosporine were used to induce dementia. The passive avoidance task was used for assessing memory. Acetylcholinesterase (AChE) activity was estimated in different parts of the brain, and immune status was studied using dinitrochlorobenzene (DNCB) skin sensitivity tests. In all the three models both aqueous and alcoholic O. sanctum extracts decreased the time taken to reach the shock-free zone and the number of mistakes and significantly decreased the AChE activity in rats. O. sanctum treatment significantly increased the induration in the DNCB skin test. Therefore, O. sanctum was shown to be useful for the management of experimentally induced cognitive dysfunctions in rats.

Modulation of doxorubicin-induced genotoxicity by squalene in Balb/c mice.

The present study aims to evaluate the protective effect of squalene against the genotoxicity of the chemotherapeutic agent doxorubicin (Dox) using two genotoxicity assays, the micronucleus assay and the comet assay. Different groups of mice were fed squalene at the doses of 1 and 4 mmol g(-1) body weight (100 or 400 µl as squalene oil) either at 4 h before or 1 h after Dox (20 mg kg(-1)) treatment. 24 h after the Dox treatment, bone marrow erythrocytes were evaluated for the incidence of micronuclei, and the induced DNA strand breaks were examined in heart tissue by the alkaline comet assay. As expected, Dox significantly induced micronuclei in polychromatic (immature) erythrocytes, as well as in total erythrocytes. The frequency of Dox-induced micronucleated erythrocytes was significantly reduced in the mice treated with squalene both before and after Dox administration. Squalene itself obviously did not induce any micronuclei in bone marrow erythrocytes. The comet assay also demonstrated a significant increase in DNA damage, especially DNA single strand breaks in the Dox-treated group of mice as compared to the control. The Dox-induced DNA damage was also effectively reduced by squalene when it was administered either before or after the Dox treatment. Squalene did not induce any significant DNA damage by itself. Compared to the pre-treatment of squalene, post treatment gave rise to more effective prevention against Dox-induced DNA damage. The data suggest that the complimentary use of squalene with Dox will be beneficial to reduce the adverse effect of Dox in cancer chemotherapy, such as the increased incidence of undesirable mutagenic side effects.