Efficacy and safety of acupuncture in the treatment of post-traumatic headache secondary to mild traumatic brain injury: A systematic evaluation and meta-analysis protocol of randomized controlled trials.

INTRODUCTION: Post-traumatic headache secondary to mild traumatic brain injury in patients has become an important factor in their prognosis. Due to the lack of effective pharmacological treatments, non-pharmacological interventions such as acupuncture are considered to have greater potential. However, the efficacy and safety of acupuncture treatment have not been clearly demonstrated. The purpose of this meta-analysis protocol is to investigate the effectiveness and safety of acupuncture in the treatment of headache secondary to mild traumatic brain injury. METHODS AND ANALYSIS: Seven English and Chinese databases will be selected and searched according to their respective search methods, spanning the period from database creation to April 2022, and the languages will be limited to English and Chinese. Only randomized controlled trials will be included. Study selection, data collection, and risk of bias control will be performed by two independent investigators. Any disagreements will be referred to a third independent investigator for decision and documentation. Revman software will be used to complete our meta-analysis, and risk of bias assessment, subgroup analysis, and sensitivity analysis will be performed to correct the results. Finally we will assess the reliability of our final results using the Recommended Guidelines Development Tool for Assessment. ETHICS AND DISSEMINATION: All data for this study will be obtained from published journals, so no ethical review will be required. The completed review will be published in a peer-reviewed journal and the findings will be further disseminated through presentation at an appropriate forum or conference.

TiO2-Nanowired Delivery of Chinese Extract of Ginkgo biloba EGb-761 and Bilobalide BN-52021 Enhanced Neuroprotective Effects of Cerebrolysin Following Spinal Cord Injury at Cold Environment.

Military personnel during combat or peacekeeping operations are exposed to extreme climates of hot or cold environments for longer durations. Spinal cord injury is quite common in military personnel following central nervous system (CNS) trauma indicating a possibility of altered pathophysiological responses at different ambient temperatures. Our previous studies show that the pathophysiology of brain injury is exacerbated in animals acclimated to cold (5 °C) or hot (30 °C) environments. In these diverse ambient temperature zones, trauma exacerbated oxidative stress generation inducing greater blood-brain barrier (BBB) permeability and cell damage. Extracts of Ginkgo biloba EGb-761 and BN-52021 treatment reduces brain pathology following heat stress. This effect is further improved following TiO2 nanowired delivery in heat stress in animal models. Several studies indicate the role of EGb-761 in attenuating spinal cord induced neuronal damages and improved functional deficit. This is quite likely that these effects are further improved following nanowired delivery of EGb-761 and BN-52021 with cerebrolysin-a balanced composition of several neurotrophic factors and peptide fragments in spinal cord trauma. In this review, TiO2 nanowired delivery of EGb-761 and BN-52021 with nanowired cerebrolysin is examined in a rat model of spinal cord injury at cold environment. Our results show that spinal cord injury aggravates cord pathology in cold-acclimated rats and nanowired delivery of EGb-761 and BN-52021 with cerebrolysin significantly induced superior neuroprotection, not reported earlier.

Nanowired Delivery of Curcumin Attenuates Methamphetamine Neurotoxicity and Elevates Levels of Dopamine and Brain-Derived Neurotrophic Factor.

Curcumin is a well-known antioxidant used as traditional medicine in China and India since ages to treat variety of inflammatory ailments as a food supplement. Curcumin has antitumor properties with neuroprotective effects in Alzheimer's disease. Curcumin elevates brain-derived neurotrophic factor (BDNF) and dopamine (DA) levels in the brain indicating its role in substance abuse. Methamphetamine (METH) is one of the most abused substances in the world that induces profound neurotoxicity by inducing breakdown of the blood-brain barrier (BBB), vasogenic edema and cellular injuries. However, influence of curcumin on METH-induced neurotoxicity is still not well investigated. In this investigation, METH neurotoxicity and neuroprotective effects of curcumin nanodelivery were examined in a rat model. METH (20 mg/kg, i.p.) neurotoxicity is evident 4 h after its administration exhibiting breakdown of BBB to Evans blue albumin in the cerebral cortex, hippocampus, cerebellum, thalamus and hypothalamus associated with vasogenic brain edema as seen measured using water content in all these regions. Nissl attaining exhibited profound neuronal injuries in the regions of BBB damage. Normal curcumin (50 mg/kg, i.v.) 30 min after METH administration was able to reduce BBB breakdown and brain edema partially in some of the above brain regions. However, TiO2 nanowired delivery of curcumin (25 mg/kg, i.v.) significantly attenuated brain edema, neuronal injuries and the BBB leakage in all the brain areas. BDNF level showed a significant higher level in METH-treated rats as compared to saline-treated METH group. Significantly enhanced DA levels in METH-treated rats were also observed with nanowired delivery of curcumin. Normal curcumin was able to slightly elevate DA and BDNF levels in the selected brain regions. Taken together, our observations are the first to show that nanodelivery of curcumin induces superior neuroprotection in METH neurotoxicity probable by enhancing BDNF and DA levels in the brain, not reported earlier.

Network pharmacological mechanism of Cinobufotalin against glioma.

OBJECTIVE: Cinobufotalin was extracted from the skin of Chinese giant salamander or black sable with good clinical effect against tumor. This study aims to explore the mechanism of Cinobufotalin components and predict the target of action of Cinobufotalin on glioma. METHODS: The active components of Cinobufotalin were screened by the Chinese medicine pharmacology database and analysis platform (TCMSP), PubChem database, etc. The potential molecular components and targets were identified and enrichment analysis was conducted through the construction of related networks and analysis of their characteristics. Relevant targets of glioma were searched through TTD, DRUGBANK, and other databases, and the intersection was found and the key targets were found too. RESULTS: A total of 21 active components and 184 target genes of Cinobufotalin were found. According to the enrichment analysis results, the pharmacological mechanism of Cinobufotalin mainly includes inhibition of the cell cycle, promotion of cell apoptosis, and regulation of immunity. On this basis, RAC1, FOS, and NOS3 can be preliminarily predicted as potential targets of Cinobufotalin in the treatment of glioma. CONCLUSIONS: The screening of active ingredients and target prediction based on network pharmacology can provide a new research idea for the multi-target treatment of glioma with Cinobufotalin.

Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke.

Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.

Glioblastoma: What can we do for these patients today and what will we be able to do in the future?

Glioblastoma multiforme (GBM) is an extremely aggressive primary human brain tumor. The median survival of GBM patients is 15 months in case of completing the modern complex treatment protocol. Chemotherapy can help to extend the life expectancy of patients. GBM treatment resistance is associated with cancer stem cells (CSCs). The present paper analyses the main reasons for ineffectiveness of the existing GBM treatment methods and suggests treating CSCs as a complex phenomenon, resulting from the coordinated interaction of normal stem cells and cancer cells (CCs) in immunosuppressive microsurroundings. The GBM treatment strategy is suggested not for only suppressing strategically important signaling pathways in CCs, but also for regulating interaction between normal stem cells and cancer cells. The paper considers the issue of controlling penetrability of the blood-brain barrier that is one of the main challenges in neuro-oncology. Also, the paper suggests the ways of extending life expectancy of GBM patients today and prospects for the near future.

Concussive head injury exacerbates neuropathology of sleep deprivation: Superior neuroprotection by co-administration of TiO2-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal stem cells.

Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (α-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of α-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of α-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in α-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-α). Exogenous administration of α-MSH (250µg/kg) together with MSCs (1×106) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO2 nanowired delivery of α-MSH (100µg), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of α-MSH and BDNF and decreased the TNF-α in SD with CHI. These observations are the first to show that TiO2 nanowired administration of α-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.

Inhibitory effect of Siwei Xiaoliuyin on glioma angiogenesis in nude mice.

OBJECTIVE: Application of Siwei Xiaoliuyin in glioma mice. Explore the effect of Siwei Xiaoliuyin on angiogenesis of nude mice glioma and its mechanism. METHODS: Establish human glioma cell line U87 tumor model. Mice were randomized to the saline group, the conventional dose of Siwei Xiaoliuyin, high dose group of Siwei Xiaoliuyin, TMZ group, combination therapy group, record the tumor volume. Using the method of Weidner counted the microvessel density. ELISA enzyme-linked adsorption method to detect the content of nude mice serum VEGF and ES. The difference was statistically significant (P<0.05). RESULTS: The tumor volume and MVD of conventional dose group, large dose group, Siwei Xiaoliuyin combined temozolomide group was smaller than the blank group，the difference was statistically significant (P<0.05). VEGF levels in three groups of nude mice were lower than the blank group and ES content is higher than blank group, the difference was statistically significant (P<0.05). CONCLUSION: Siwei Xiaoliuyin can inhibit glioma angiogenesis. Its mechanism of glioma angiogenesis inhibition may be through regulation VEGF and down-regulation of endostatin expression of vascular endothelial growth factor achieved. Down-regulation of endostatin expression of vascular endothelial growth factor achieved.

New advances on the inhibition of Siwei Xiaoliuyin combined with Temozolomide in glioma based on the regulatory mechanism of miRNA21/221.

OBJECTIVE: To provide evidence for the mechanism of Chinese medicine to treat glioma. We observe the effects of Si wei xiao xiu yin combined with chemotherapy on the growth of subcutaneous xenografts in nude mice and the expression of miRNA-21 and miRNA-221 in tumor tissues. METHODS: The subcutaneous transplantation model of nude mice was established by subcutaneous inoculation of glioma U87 cell suspension. They were randomly divided into saline group, traditional Chinese medicine group, temozolomide group and traditional Chinese medicine combined with temozolomide group to observe the changes in body weight, and the tumor weight, length, short diameter, volume of mice. The relative expression levels of miRNA-21 and miRNA-221 in tumor tissues were detected by qRT-PCR, and the differences between groups were compared. RESULTS: After 28 days of gavage, the tumor growth of the other three groups was slower than that of saline group, and the difference was most significant in the combination group (P=0.008<0.05), besides, the relative expression of the three groups of miRNA-21 and miRNA-221 was significantly inhibited compared with saline group, and the difference was significant in the combination group (F=8.918, P=0.010<0.05). CONCLUSION: To some extent, Si wei xiao xiu yin combined with temozolomide can inhibit the growth of subcutaneous xenografts in glioma nude mice. The mechanism may be related to the inhibition of miRNA-21 and miRNA-221 expression.

Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease.

More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AßP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AßP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.

Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury: Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/51.

Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.

Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord.

Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.

Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain.

The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier.

PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury.

Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil-in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 ± 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration.

The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions. However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition. Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.

New perspectives of nanoneuroprotection, nanoneuropharmacology and nanoneurotoxicity: modulatory role of amino acid neurotransmitters, stress, trauma, and co-morbidity factors in nanomedicine.

Recent advancement in nanomedicine suggests that nanodrug delivery using nanoformulation of drugs or use of nanoparticles for neurodiagnostic and/or neurotherapeutic purposes results in superior effects than the conventional drugs or parent compounds. This indicates a bright future for nanomedicine in treating neurological diseases in clinics. However, the effects of nanoparticles per se in inducing neurotoxicology by altering amino acid neurotransmitters, if any, are still being largely ignored. The main aim of nanomedicine is to enhance the drug availability within the central nervous system (CNS) for greater therapeutic successes. However, once the drug together with nanoparticles enters into the CNS compartments, the fate of nanomaterial within the brain microenvironment is largely remained unknown. Thus, to achieve greater success in nanomedicine, our knowledge in understanding nanoneurotoxicology in detail is utmost important. In addition, how co-morbidity factors associated with neurological disease, e.g., stress, trauma, hypertension or diabetes, may influence the neurotherapeutic potentials of nanomedicine are also necessary to explore the details. Recent research in our laboratory demonstrated that engineered nanoparticles from metals or titanium nanowires used for nanodrug delivery in laboratory animals markedly influenced the CNS functions and alter amino acid neurotransmitters in healthy animals. These adverse reactions of nanoparticles within the CNS are further aggravated in animals with different co-morbidity factors viz., stress, diabetes, trauma or hypertension. This effect, however, depends on the composition and dose of the nanomaterials used. On the other hand, nanodrug delivery by TiO2 nanowires enhanced the neurotherapeutic potential of the parent compounds in CNS injuries in healthy animals and do not alter amino acids balance. However, in animals with any of the above co-morbidity factors, high dose of nanodrug delivery is needed to achieve some neuroprotection. Taken together, it appears that while exploring new nanodrug formulations for neurotherapeutic purposes, co-morbidly factors and composition of nanoparticlesrequire more attention. Furthermore, neurotoxicity caused by nanoparticles per se following nanodrug delivery may be examined in greater detail with special regards to changes in amino acid balance in the CNS.

Quercetin in hypoxia-induced oxidative stress: novel target for neuroprotection.

Oxidative stress in the central nervous system is one of the key players for neurodegeneration. Thus, antioxidants could play important roles in treating several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and aging-related brain disorders. This review is focused on the new developments in oxidative stress-induced neurodegeneration. Further, based on our own investigations, new roles of quercetin, an antioxidant compound in hypoxia and ischemia induced neuroprotection in relation to suppression of oxidative stress, improvement in behavioral function, reduction in infarct volume, brain swelling, and cellular injury in both in vivo and in vitro models are discussed. Our new findings clearly suggest that antioxidant compounds have potential role in therapeutic strategies to treat neurodegenerative diseases in clinical settings.

Antifertility effect of Tinospora cordifolia (Willd.) stem extract in male rats.

Oral administration of 70% methanolic extract of T. cordifolia stem to male rats at the dose level of 100 mg/rat/day for 60 days did not cause body weight loss but decreased the weight of testes, epididymis, seminal vesicle and ventral prostate in a significant manner. Sperm motility as well as sperm density were reduced significantly which resulted in reduction of male fertility by 100%. The stem extract brought about an interference with spermatogenesis. The round spermatids were decreased by 73.12%. However, the population of preleptotene and pachytene spermatocytes were decreased by 47.60% and 52.85% respectively, followed by secondary spermatocytes (48.10%). Leydig cell nuclear area and mature Leydig cell numbers were significantly reduced when compared with controls. Serum testosterone levels showed significant reduction after Tinospora extract feeding. Seminiferous tubule diameter, Leydig cell nuclear area as well as cross sectional surface area of Sertoli cells were reduced significantly when compared to controls. Biochemical parameters i.e. protein, sialic acid, glycogen contents of testes decreased significantly. Seminal vesicular fructose also depleted whereas, testicular cholesterol was elevated significantly followed by a reduction in testosterone levels. These results suggested antifertility effects of the stem extract of T. cordifolia in male rats.

Effect of Alstonia scholaris bark extract on testicular function of Wistar rats.

AIM: To evaluate the antifertility effect of Alstonia scholaris bark extract in male rats. METHODS: In male Wistar rats Alstonia scholaris bark extract was given by oral route at a dose of 200 mg/day for 60 days. The fertility and testicular function were assessed by mating tests, sperm motility, sperm concentration, biochemical indices and testicular cell population dynamics. RESULTS: Oral feeding with the extract at a dose of 200 mg/day for the period of 60 days did not cause body weight loss, while the weights of testes, epididymides, seminal vesicle and ventral prostate were significantly reduced. The production of step-19 spermatids was reduced by 79.6% in treated rats. The population of preleptotene and pachytene spermatocytes were decreased by 61.9% and 60.1%, respectively. Spermatogonia and Sertoli cell population were also affected. The seminiferous tubule and Leydig cell nuclear area were reduced significantly (P<0.01) when compared to the controls. Reduced sperm count and motility resulted in a total suppression of fertility. A significant fall in the protein and sialic acid content of the testes, epididymides, seminal vesicle and ventral prostate as well as glycogen content of testes were also noticed. The fructose content in the seminal vesicle was lowered whereas the testicular cholesterol was elevated as compared with the controls. The following compounds were obtained from the extract with chromatographic separation over Si-gel column: agr-amyrin, bgr-amyrin, lupiol acetate, venenative, rhazine and yohimbine. CONCLUSION: At the dose level employed, Alstonia scholaris bark extract has a significant antifertility effect in male rats; the primary site of action may be post meiotic germ cells (Step 19 spermatids).