Lead (Pb) exposure induces physiological alterations in the serotoninergic and vasopressin systems causing anxiogenic-like behavior in Meriones shawi: Assessment of BDMC as a neuroprotective compound for Pb-neurotoxicity and kidney damages.

BACKGROUND: Studies have shown that lead (Pb) is one of hazardous heavy metals with various adverse effects on human health including mental health; Pb can induce psychiatric disorders like anxiety. In the present work, we examined the potential of bisdemethoxycurcumin (BDMC) as a neuroprotective agent against lead induced anxiety inMeriones shawi (M. shawi). METHODS: We asses, the potential of three consecutive day exposure to Pb (25 mg/kg body weight) in inducing anxiogenic effect, serotoninergic and vasopressinergic disruptions inM. shawi. This was done using neurobehavioral tests (open field, elevated plus maze), immunohistochemestry by anti-serotonin (5-HT), and anti-vasopressin (AVP) antibodies. We also measured the possible restorative potential of BDMC (30 mg/kg body weight), delivered by oral gavage. After that, a biochemical and histopathological studies were done. RESULTS: Our results showed that lead exposure for three consecutive days increases significantly the 5-HT-immunoreactivity in dorsal raphe nucleus (DRN) accompanied with a significant enhancement of AVP-immunoreactivity in the cell bodies and fibers in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. In the collecting tube, AVP binds to the V2 receptor of the epithelial cells and increases the water permeability. Our results showed clearly the epithelial cells degeneration after lead exposure, then we suggest that the increased AVP could be a response to the hydric balance disrupted after degenerative effect of lead exposure on epithelial cells. BDMC produced an anxiolytic effect in meriones. Moreover, it restored 5-HT and AVP immunoreactivity within studying nuclei. The biochemical and histopathological studies showed that Pb induced renal damages. In addition, BDMC restored the renal alterations. CONCLUSION: According to the obtained results, we suggest new pharmacological effects of BDMC; while it has an anxiolytic effect against Pb-induced anxiety by working on serotoninergic and vasopressinergic systems with an obvious restoration of the renal injuries induced by lead exposure.

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2 (AAV2)-human GDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8 × 108, 6.8 × 109, or 5.2 × 1010 vector genomes (vg)/dose followed by interim sacrifices on day 7, 31, 90, and 376. There were no treatment-related effects observed on food consumption, body weight, hematology, clinical chemistry, coagulation parameters, neurobehavioral parameters, organ weights, or serum GDNF and anti-GDNF antibody levels. Increased serum anti-AAV2 neutralizing antibody titers were observed in the 5.2 × 1010 vg/dose group. Histopathological lesions were observed at the injection site in the 6.8 × 109 vg/dose (day 7) and 5.2 × 1010 vg/dose groups (days 7 and 31) and consisted of gliosis, mononuclear perivascular cuffing, intranuclear inclusion bodies, and/or apoptosis on day 7 and mononuclear perivascular cuffing on day 31. GDNF immunostaining was observed in the injection site in all dose groups through day 376 indicating no detectable impacts of anti-AAV2 neutralizing antibody. There was no evidence of increased expression of calcitonin gene-related peptide or Swann cell hyperplasia in the cervical and lumbar spinal cord or medulla oblongata at the 5.2 × 1010 vg/dose level indicating lack of hyperplastic effects. In conclusion, no systemic toxicity was observed, and the local toxicity observed at the injection site appeared to be reversible demonstrating a promising safety profile of intracerebral AAV2-GDNF delivery. Furthermore, an intracerebral dose of 6.8 × 108 AAV2-GDNF vg/dose was considered to be a no observed adverse effect level in rats.

Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety.

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70 years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer's disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

Protective effects of combined treatment with mild hypothermia and edaravone against cerebral ischemia/reperfusion injury via oxidative stress and Nrf2 pathway regulation.

Mild hypothermia (MH) and edaravone (EDA) exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury through activation of the nuclear factor erythroid 2­related factor 2 (Nrf2) pathway. However, whether MH and EDA exert synergistic effects against cerebral I/R injury remains unknown. The aim of the present study was to investigate the effects and mechanism of action of MH in combination with EDA in cerebral I/R injury. A rat cerebral I/R injury model was constructed by middle cerebral artery occlusion (MCAO) followed by reperfusion, and the mice were treated by MH, EDA or the inhibitor of the Nrf2 signaling pathway brusatol (Bru). It was observed that mice treated by MCAO had higher neurological deficit scores and oxidative stress levels, and low spatial learning and memory capacity; moreover, the CA1 region of the hippocampi of the mice exhibited reduced neuronal density and viability, and reduced mitochondrial dysfunction. However, MH in combination with EDA reversed the effects of MCAO, which were blocked by Bru injection. The levels of glutathione (GSH), GSH peroxidase, catalase and superoxide dismutase in rat ischemic hemisphere tissues were reduced by Bru. Western blotting demonstrated that the combined treatment with MH and EDA promoted the nuclear localization of Nrf2, and increased the levels of NAD(P)H quinone oxidoreductase and heme oxygenase (HO)­1. In conclusion, MH combined with EDA exerted synergistic neuroprotective effects against cerebral I/R injury involving changes in the Nrf2/HO­1 pathway.

Neuroprotective effect of Convolvulus pluricaulis Choisy in oxidative stress model of cerebral ischemia reperfusion injury and assessment of MAP2 in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Convolvulus pluricaulis Choisy commonly known as Shankhapushpi, is traditionally prescribed for nerve debility, loss of memory, epilepsy and as nervine tonic. Plant also proved to have diverse pharmacological activity but the neuroprotection in ischemic stroke were not found. AIM OF THE STUDY: To investigate the effect of Convolvulus pluricaulis against bilateral common carotid artery (BCCA) occlusion induced cerebral ischemic reperfusion injury. MATERIALS AND METHODS: The neuroprotective activity of Convolvulus pluricaulis against bilateral common carotid artery (BCCA) occlusion induced cerebral ischemic reperfusion (I/S) injury. Sprague-Dawley rats of either sex (200-250 g) were divided into nine groups of 8 rats each. Sham and control group, saline treated 10 ml/kg orally. Third group treated with Quercetin 25 mg/kg orally and fourth to ninth groups treated with chloroform and ethanol extract of Convolvulus pluricaulis 100, 200, and 400 mg/kg (p.o.) respectively. Control, Quercetin and extract treated groups underwent 30 min BCCA occlusion and 24 h reperfusion on 10th day but sham underwent same surgery without BCCA occlusion and 24 h reperfusion on 10th day. The antioxidant enzymatic and non-enzymatic levels were estimated by UV spectroscopic method and cerebral infarction area, Blood brain barrier disruption, microtubule-associated protein 2 immunohistochemical and histopathological studies were carried out. RESULTS: The results of the study indicate that the chloroform and ethanol extract of Convolvulus pluricaulis showed neuroprotective activity by a significant decrease in lipid peroxidation (p < 0.001) and an increase in superoxide dismutase (p < 0.01, p < 0.001), catalase (p < 0.01, p < 0.001), glutathione (p < 0.001), and total thiol (p < 0.001) levels in extract-treated groups as compared to control group. Measurement of cerebral infarction area, blood brain barrier disruption, microtubule-associated protein 2 immunohistochemical and histopathological studies further supported the protective effect of the extract. CONCLUSIONS: Present study revile that Convolvulus pluricaulis has potent neuroprotection against bilateral common carotid artery (BCCA) occlusion induced cerebral ischemic reperfusion injury.

Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants.

There is significant uncertainty over the role of assessment of long-term neurodevelopmental outcome (LTO) in neonatal clinical trials. A multidisciplinary working group was established to identify key issues in this area and to make recommendations about optimal approaches to evaluate LTO in therapeutic trials in newborns, which can be developed by sponsors and investigators with other key stakeholders. A key consideration for neonatal trials is the potential for the investigational product to cause widespread effects and drives the need to assess outcome in multiple organs. Thus investigators must assess whether the product has an impact on the brain and the potential for it to cause potential effects on LTO. Critically, is assessment of LTO an important direct therapeutic target or a safety outcome? Such decisions and outcomes need to be specific to the product being studied and use published data, only considering expert opinion when prior evidence does not exist. In designing the trial, the balance of benefits, costs, and burdens of assessments to the researcher and families need to be considered. Families and parent advocates should be involved in design and execution of the study. A framework is presented for use by all key stakeholders to determine the need, nature, and duration of LTO assessments in regulatory trials involving newborn infants.

A behavioral economic analysis of the effects of rimcazole on reinforcing effects of cocaine injection and food presentation in rats.

RATIONALE AND OBJECTIVES: Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects. METHODS: Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q0) and sensitivity to price (essential value, EV), derived. RESULTS: Rimcazole dose-dependently decreased Q0 and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. CONCLUSIONS: Though the drug combinations only replicated rimcazole's effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.

No. 376-Magnesium Sulphate for Fetal Neuroprotection.

OBJECTIVE: The objective is to provide guidelines for the use of antenatal magnesium sulphate for fetal neuroprotection of the preterm infant. OPTIONS: Antenatal magnesium sulphate administration should be considered for fetal neuroprotection when women present at ≤33 + 6 weeks with imminent preterm birth, defined as a high likelihood of birth because of active labour with cervical dilatation ≥4 cm, with or without preterm pre-labour rupture of membranes, and/or planned preterm birth for fetal or maternal indications. There are no other known fetal neuroprotective agents. OUTCOMES: The outcomes measured are the incidence of cerebral palsy (CP) and neonatal death. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library in December 2017, using appropriate controlled vocabulary and key words (magnesium sulphate, cerebral palsy, preterm birth). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Antenatal magnesium sulphate for fetal neuroprotection reduces the risk of "death or CP" (relative risk [RR] 0.85; 95% confidence interval [CI] 0.74-0.98; 4 trials, 4446 infants), "death or moderate-severe CP" (RR 0.85; 95% CI 0.73-0.99; 3 trials, 4250 infants), "any CP" (RR 0.71; 95% CI 0.55-0.91; 4, trials, 4446 infants), "moderate-to-severe CP" (RR 0.60; 95% CI 0.43-0.84; 3 trials, 4250 infants), and "substantial gross motor dysfunction" (inability to walk without assistance) (RR 0.60; 95% CI 0.43-0.83; 3 trials, 4287 women) at 2 years of age. Results were consistent between trials and across the meta-analyses. There is no anticipated significant increase in health care-related costs because women eligible to receive antenatal magnesium sulphate will be judged to have imminent preterm birth. VALIDATION: Australian National Clinical Practice Guidelines were published in March 2010 by the Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. Antenatal magnesium sulphate was recommended for fetal neuroprotection in the same dosage as recommended in these guidelines. However, magnesium sulphate was recommended only at <30 weeks gestation, based on 2 considerations. First, no single gestational age subgroup was considered to show a clear benefit. Second, in the face of uncertainty, the committee felt it was prudent to limit the impact of their clinical practice guidelines on resource allocation. In March 2010, the American College of Obstetricians and Gynecologists issued a Committee Opinion on magnesium sulphate for fetal neuroprotection. It stated that "the available evidence suggests that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants." No official opinion was given on a gestational age cut-off, but it was recommended that physicians develop specific guidelines around the issues of inclusion criteria, dosage, concurrent tocolysis, and monitoring in accordance with 1 of the larger trials. Similarly, the World Health Organization also strongly recommends use of magnesium sulphate for fetal neuroprotection in its 2015 recommendations on interventions to improve preterm birth outcomes but cites further researching on dosing regimen and re-treatment. SPONSORS: Canadian Institutes of Health Research (CIHR). SUMMARY STATEMENT: RECOMMENDATIONS.

Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and α-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer's disease: Are combinations more effective?

Increasingly, evidence is accumulating pointing at a protective role of a healthy diet at decreasing the risk of Alzheimer's disease. To test the effectiveness of nutritional components, the following food-derived compounds: curcumin alone (curcumin), curcumin combined with (-)epigallocatechin-3-gallate (EGCG), docosahexaenoic acid (DHA) and α-lipoic acid (ALA) (curcumin + EDA), or a combination of EGCG, DHA and ALA (EDA) were assessed in male Tg2576 transgenic mice on amyloid plaque load, amyloid levels (Aß40/Aß42, but not oligomers due to tissue limitations), microglial activation and memory using the contextual and cued fear conditioning test. The combination diet EDA, resulted in the strongest reduction of amyloid plaque load in both the cortical (p < .0001) and hippocampal (p < .0001) areas of the Tg2576 mouse brain, along with lower Aß40/Aß42 levels in the frontal cortex (p = .000129 and p = .000039, respectively) and Aß42 levels in the temporal lobe (p = .000082). A curcumin only diet was shown to lower amyloid plaque load (p = .028), but when combined with EGCG, DHA and ALA did not result in further decreases in amyloid plaque load. The EDA combination group showed the most prominent decrease in microglial activation (number of microglia around plaques: p < .05 and p < .0001, respectively, for the cortex and hippocampus). Analysing the hippocampal associated contextual fear conditioning revealed that both the curcumin+EDA (p < .0001) and EDA groups (p = .001) spent increased time on freezing compared to the control group. In addition, the curcumin+EDA group showed a significant increase in time spent freezing compared with the curcumin only group. In the amygdala associated cued test, all mice demonstrated the ability to associate the conditioned stimulus with the unconditioned stimulus as evidenced by a significant increase in freezing behaviour in response to the presentation of the cue (p < .0001). Post-hoc analysis showed that only curcumin+EDA (p < .0001) and EDA groups (p < .0001) developed a significant increase in freezing during the cue presentation. The results from this study show that the combination of EGCG, DHA and ALA (EDA) appeared to have the most potent anti-inflammatory and neuroprotective effect. Our results also demonstrate that interactions between nutraceutical products might result in counterproductive outcomes, highlighting the fact that manufacturers of nutraceuticals containing multiple compounds should be careful not to claim additive or synergistic effects of their combination products in vivo without having tested it in animal models and/or human clinical trials.

Protection of brain development by antenatal magnesium sulphate for infants born preterm.

Cerebral palsy (CP) remains the most significant neurological disorder associated with preterm birth. It disrupts quality of life and places huge cost burdens on society. Antenatal magnesium sulphate administration to females before 32 weeks' gestation has proven to be an effective intervention to reduce the rate of CP. In models of hypoxia, hypoxia-ischemia, inflammation, and excitotoxicity in various animal species, magnesium sulphate preconditioning decreased the resulting lesion sizes and inflammatory cytokine levels, prevented cell death, and improved long-term cognitive and motor behaviours. In humans, meta-analyses of five randomized controlled trials using magnesium sulphate as a neuroprotectant showed prevention of CP at 2 years. The benefit remained consistent regardless of gestational age, cause of preterm birth, and total dose received. Antenatal magnesium sulphate treatment is now recommended by the World Health Organization and by many obstetric societies. Its cost-effectiveness further justifies its widespread implementation. WHAT THIS PAPER ADDS: Neuroprotective effect of magnesium sulphate to reduce cerebral palsy in infants born preterm when administered to females at risk of imminent preterm birth. Neuroprotection regardless of gestational age, cause of preterm birth, and total dose. Antenatal magnesium sulphate treatment has good cost-effectiveness.

Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aß), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model. MATERIALS AND METHODS: In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aß42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-ß precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas one group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined. RESULTS: Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner. CONCLUSION: Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD.

Lycium barbarum polysaccharide encapsulated Poly lactic-co-glycolic acid Nanofibers: cost effective herbal medicine for potential application in peripheral nerve tissue engineering.

Nerve regeneration is a serious clinical challenge following peripheral nerve injury. Lycium barbarum polysaccharide (LBP) is the major component of wolfberry extract, which has been shown to be neuroprotective and promising in nerve recovery in many studies. Electrospun nanofibers, especially core-shell structured nanofibers being capable of serving as both drug delivery system and tissue engineering scaffolds, are well known to be suitable scaffolds for regeneration of peripheral nerve applications. In this study, LBP was incorporated into core-shell structured nanofibrous scaffolds via coaxial electrospinning. Alamar blue assays were performed to investigate the proliferation of both PC12 and Schwann cells cultured on the scaffolds. The neuronal differentiation of PC12 cells was evaluated by NF200 expression with immunostaining and morphology changes observed by SEM. The results indicated that the released LBP dramatically enhanced both proliferation and neuronal differentiation of PC12 cells induced by NGF. Additionally, the promotion of Schwann cells myelination and neurite outgrowth of DRG neurons were also observed on LBP loaded scaffolds by LSCM with immunostaining. In summary, LBP, as a drug with neuroprotection, encapsulated into electrospun nanofibers could be a potential candidate as tissue engineered scaffold for peripheral nerve regeneration.

Assessment of systemic administration of PEGylated IGF-1 in a mouse model of traumatic brain injury.

BACKGROUND: Traumatic brain injury can result in lasting cognitive dysfunction due to degeneration of mature hippocampal neurons as well as the loss of immature neurons within the dentate gyrus. While endogenous neurogenesis affords a partial recovery of the immature neuron population, hippocampal neurogenesis may be enhanced through therapeutic intervention. Insulin-like growth factor-1 (IGF-1) has the potential to improve cognitive function and promote neurogenesis after TBI, but its short half-life in the systemic circulation makes it difficult to maintain a therapeutic concentration. IGF-1 modified with a polyethylene glycol moiety (PEG-IGF-1) exhibits improved stability and half-life while retaining its ability to enter the brain from the periphery, increasing its viability as a translational approach. OBJECTIVE: The goal of this study was to evaluate the ability of systemic PEG-IGF-1 administration to attenuate acute neuronal loss and stimulate the recovery of hippocampal immature neurons in brain-injured mice. METHODS: In a series of studies utilizing a well-established contusion brain injury model, PEG-IGF-1 was administered subcutaneously after injury. Serum levels of PEG were verified using ELISA and histological staining was used to investigate numbers of degenerating neurons and cortical contusion size at 24 h after injury. Immunofluorescent staining was used to evaluate numbers of immature neurons at 10 d after injury. RESULTS: Although subcutaneous injections of PEG-IGF-1 increased serum IGF-1 levels in a dose-dependent manner, no effects were observed on cortical contusion size, neurodegeneration within the dentate gyrus, or recovery of hippocampal immature neuron numbers. CONCLUSIONS: In contrast to its efficacy in rodent models of neurodegenerative diseases, PEG- IGF-1 was not effective in ameliorating early neuronal loss after contusion brain trauma.

Assessment of the neuroprotective effects of the acetylcholinesterase inhibitor huperzine A in an experimental spinal cord trauma model.

BACKGROUND: Spinal cord injury is nowadays still a challenging disease, and a treatment option aimed at the primary site of injury does not currently exist. Therefore, the management of acute spinal cord injury has recently focused on the reasons behind the aggravation of the initial insult through secondary mechanisms, and the search for pharmacological treatment protocols is generally aimed at reducing and minimizing the neural injury and neurological sequela. The secondary spinal cord injury usually develops following a primary lesion induced by spinal cord contusion and the emergence of apoptotic cells has been found to play an important role in the development of secondary injury. We propose that huperzine A may induce a significant reduction in the number of apoptotic cells because it possesses the ability to protect cells against glutamate, ischemia and staurosporine-induced cytotocity and apoptosis. METHODS: Huperzine A was administered intraperitoneally to male Wistar Albino rats (220-340 g of body weight) after moderate static clip compression (70 g for 60 s) of the spinal cord at T7 level. Neurological functions were assessed using the Basso-Beattle-Breshanan (BBB) motor rating scale until 3th and 7th days before perfusion, following which the spinal cord was harvested for histopathological examinations and apoptotic cell counts. RESULTS: Histopathological evaluations of the spinal cord of the control, trauma and huperzine A treated groups were evaluated. Control group showed normal neuronal and vascular structures of the spinal cord. However, in both trauma groups 3rd- and 7th-day perfusion showed extensive cavitation and hemorrhage, areas of necrosis and edema in gray matter, and degeneration in motor neurons along with patchy areas of necrotic and apoptotic cells. In the group treated with huperzine A, an increased number of normal cells was observed, along with a lower number of necrotic cells, with a significant reduction in the apoptotic cells (P<0.01). The administration of huperzine A improved post-trauma motor performance. Furthermore, BBB scores of all groups showed that there was an improvement of locomotor abilities in the treatment group as compared with the control. CONCLUSIONS: When compared with controls, huperzine A treatment demonstrates a significant reduction in the number of apoptotic cells. In addition, the group treated with huperzine A showed significant and appreciable neurological improvement in rats.

Innovations in Liposomal DDS Technology and Its Application for the Treatment of Various Diseases.

Liposomes have been widely used as drug carriers in the field of drug delivery systems (DDS), and they are thought to be ideal nano-capsules for targeting DDS after being injected into the bloodstream. In general, DDS drugs meet the needs of aged and super-aged societies, since the administration route of drugs can be changed, the medication frequency reduced, the adverse effects of drugs suppressed, and so on. In fact, a number of liposomal drugs have been launched and used worldwide including liposomal anticancer drugs, and these drugs have appeared on the market owing to various innovations in liposomal DDS technologies. The accumulation of long-circulating liposomes in cancer tissue is driven by the enhanced permeability and retention (EPR) effect. In this review, liposome-based targeting DDS for cancer therapy is briefly discussed. Since cancer angiogenic vessels are the ideal target of drug carriers after their injection and are critical for cancer growth, damaging of these neovessels has been an approach for eradicating cancer cells. Also, the usage of liposomal DDS for the treatment of ischemic stroke is possible, since we observed that PEGylated liposomes accumulate in the site of cerebral ischemia in transient middle cerebral artery occlusion (t-MCAO) model rats. Interestingly, liposomes carrying neuroprotectants partly suppress ischemia/reperfusion injury of these model rats, suggesting that the EPR effect also works in ischemic diseases by causing an increase in the permeability of the blood vessel endothelium. The potential of liposomal DDS against life-threatening diseases might thus be attractive for supporting long-lived societies.

Assessment of pharmacokinetic interaction between piracetam and l-carnitine in healthy subjects.

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d-8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one-step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5-50 µg/mL (r > 0.99). This LC-MS-MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l-carnitine (Piracar®; 270/330 mg tablet) and piracetam (Nootropil®; 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 - 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 - 104.51) for AUCinf /dose. The limit of quantitation of 0.5 µg/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar®; 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil®; 800 mg tablet) formulation with regard to both the rate and the extent of absorption.

Assessment of C-phycocyanin effect on astrocytes-mediated neuroprotection against oxidative brain injury using 2D and 3D astrocyte tissue model.

Drugs are currently being developed to attenuate oxidative stress as a treatment for brain injuries. C-phycocyanin (C-Pc) is an antioxidant protein of green microalgae known to exert neuroprotective effects against oxidative brain injury. Astrocytes, which compose many portions of the brain, exert various functions to overcome oxidative stress; however, little is known about how C-Pc mediates the antioxidative effects of astrocytes. In this study, we revealed that C-Pc intranasal administration to the middle cerebral artery occlusion (MCAO) rats ensures neuroprotection of ischemic brain by reducing infarct size and improving behavioral deficits. C-Pc also enhanced viability and proliferation but attenuated apoptosis and reactive oxygen species (ROS) of oxidized astrocytes, without cytotoxicity to normal astrocytes and neurons. To elucidate how C-Pc leads astrocytes to enhance neuroprotection and repair of ischemia brain, we firstly developed 3D oxidized astrocyte model. C-Pc had astrocytes upregulate antioxidant enzymes such as SOD and catalase and neurotrophic factors BDNF and NGF, while alleviating inflammatory factors IL-6 and IL-1ß and glial scar. Additionally, C-Pc improved viability of 3D oxidized neurons. In summary, C-Pc was concluded to activate oxidized astrocytes to protect and repair the ischemic brain with the combinatorial effects of improved antioxidative, neurotrophic, and anti-inflammatory mechanisms.

Histopathological, ultrastructural, and immunohistochemical assessment of hippocampus structures of rats exposed to TCDD and high doses of tocopherol and acetylsalicylic acid.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP) and acetylsalicylic acid (ASA) on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system.