Cross Blood Brain Barrier Research Articles

Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation–predominant irritable bowel syndrome

BackgroundIntestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. Methods72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. ResultsBoth drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide).Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). ConclusionSystemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.

Odorranalectin modified PEG–PLGA/PEG–PBLG curcumin-loaded nanoparticle for intranasal administration

Curcumin (Cur) is a promising drug for neurological diseases. Nevertheless, the application of Cur has been limited due to its difficulty in penetrating blood-brain barrier (BBB). Intranasal drug delivery, a noninvasive alternative delivery of Cur, can effectively help Cur cross BBB and inert into central nervous system directly. Odorranalectin (OL) which is the smallest lectin can prolong the residence time of Cur in the nasal mucosa and promote cellular uptake. In this work, a nasal delivery system incorporating OL modified Cur-loaded nanoparticles (Cur–OL–NPs) was developed and expected to bypass BBB and promote the absorption of Cur. We conjugated OL to polyethylene glycol-poly (lactic-co-glycolic acid) (PEG–PLGA), and combined polyethylene glycol-poly (γ-benzyl-L-glutamate) (PEG–PBLG) and OL–PEG–PLGA to prepare nanoparticles to improve the stability, bioavailability and targeting of Cur. Compared with unmodified NPs, increased efficiency of Cur–OL–NPs cellular uptake by Calu-3 cells had been obtained with no severe toxicity. Furthermore, in vivo pharmacokinetic studies also showed that Cur–OL–NPs had higher relative bioavailability. Thus, it is concluded that the results indicated that OL–NPs as carriers of Cur had a promising future in nasal drug delivery system.

Repolarization of glioblastoma macrophage cells using non-agonistic Dectin-1 ligand encapsulating TLR-9 agonist: plausible role in regenerative medicine against brain tumor

Aim of the study Glioblastoma multiforme (GBM) is the most severe forms of brain cancer, eventually becoming the leading cause of brain cancer-related death worldwide. Owing to the bleak surgical interventions and resistance to the different treatment regime, GBM is a parlous disease demanding newer therapeutical perspective for its treatment. Toll-like receptors (TLRs) are well-known members of pathogen recognition receptors (PRRs) and have been extensively explored for their therapeutic and prophylactic potential in an array of disease including cancer. Recent trends in drug delivery research has shown shift towards delivering short DNA sequences (CpG DNA) to endosomal TLR9 within immune cells (macrophages, dendritic cells, etc.) for the activation of desired inflammatory response using non-agonistic β-glucan particles; a well-known ligand for Dectin-1 receptors. Our study is therefore focused to explore the role of nano-encapsulated CpG ODN as critical players in polarizing M2 scavenging to much desired pro-inflammatory type. Materials and methods The nanoparticles entrapping CpG ODN 1826 were prepared by using a fungal polymer Schizophyllan (SPG). The constructed nanoparticles were characterized and assessed for their efficacy on rat glioblastoma cells (C6). Results The constructed Schizophyllan (SPG) nanoparticles entrapping CpG ODN 1826 (95.3%) were of 25.49 nm in diameter and thus capable of crossing blood–brain barrier. The rat glioblastoma (C6) cells evaluated for intracellular oxidative burst and cytokine levels pre- and post-incubation with nanoparticles exhibited marked elevation in the expression of intracellular ROS and IFN-γ as well as IL-1β post treatment. Conclusion The findings indicate towards potentiality of repolarizing the M2 macrophages to much desired M1 phase by inducing higgh levels of oxidative burst and inflammatory cytokines. Consequently, the apoptosis was induced in glioblastoma cells establishing the suitablity of CpG ODN carrying nanoformulations as emerging therapeutic intervention for GBM.

Modification of curcumin-loaded liposome with edible compounds to enhance ability of crossing blood brain barrier

This research explored the potential of food grade sialic acid (SA), polymerized SA (PSA), and their oxidized form to conjugate with wheat germ agglutinin (WGA) on liposome to deliver curcumin to brain. Results showed that curcumin was entrapped in liposome with high encapsulation efficiency (90.77%) and the vector had a size of about 115 nm in diameter. The thermogravimetric analysis (TGA) confirmed the successful presence of SA and PSA in the lipid bilayers of liposomes. The TGA curves below 100 °C suggested that WGA acts as a protective layer for SA and PSA. In general, the liposomes modified by the un-oxidized SA or PSA could conjugate more WGA than that oxidized counterparts, and polymerization of SA did not increase WGA conjugation on the liposomes. More than 40% of WGA on the surface of modified liposomes remained after digestive enzymes challenge. The amide peaks at 1241 cm-1 and 533-581 cm-1 in the Fourier transform infrared (FTIR) spectrum of the modified liposomes indicated the covalent bonding between carboxyl group of SA and amine group of WGA. These characteristic peaks still existed after digestive enzymes challenge, demonstrating that the conjugation of WGA and SA on the modified liposome can resist the digestive enzymes to a certain extent. SEM images showed that the modified liposomes after digestive enzymes treatment were still spherical with clear rim, and the enzyme-treated vectors had a higher permeation rate crossing blood-brain barrier (BBB) endothelial cell monolayer than the un-modified liposome without enzyme treatment. This study demonstrates how the surface modification can enhance the function of liposome as a phytochemical carrier for brain disease.

Molecular Probe Crossing Blood–Brain Barrier for Bimodal Imaging–Guided Photothermal/Photodynamic Therapies of Intracranial Glioblastoma

AbstractCurrently, treatment of intracranial diseases still remains a great challenge because the blood–brain barrier (BBB) blocks access of most drugs to the central nervous system. Herein, a theranostic small molecular probe, iRGD‐ICG‐Lys‐DTPA@Gd (iRGD‐ILD), capable of crossing BBB is developed. Owing to the small molecular size and αvβ3 integrin receptor–mediated transcytosis, this tailor‐made molecular probe integrating the fluorescence and magnetic resonance imaging functions effectively passes through BBB to target tumor cells even in the early stage of glioblastoma multiforme (GBM), thereby allowing a bimodal imaging–guided therapy of GBM. The reactive oxygen species and heat generated by the ICG moiety under the 808 nm laser irradiation exert photodynamic/photothermal therapeutic effects, which results in significantly inhibited tumor growth and prolonged median survival of C6‐Luc glioma‐bearing mice. Notably, the integration of FDA‐approved clinically available agents, e.g., ICG, DTPA and Gd, into a molecular probe may ensure desirable biocompatibility and biosafety for in vivo applications. Overall, the results highlight the potential of a water‐soluble small molecule as a novel theranostic probe for highly effective GBM treatment.

A study of complications of chronic suppurative otitis media at tertiary care hospital

<p class="abstract"><strong>Background:</strong> Chronic suppurative otitis media (CSOM) is a still common disease in developing country and is found sometimes difficult to treat. Different complications can develop inspite of availability of higher antibiotics. In pre-antibiotic era, complications of acute otitis media and CSOM were very common and lead to high mortality. Inspite of initial decline in the complication of CSOM due to higher antibiotics, the incidences are still on rise. CSOM remains a serious disease, particularly in developing countries and CSOM-related complications are still found life-threatening. The aim and objective was to study various clinical presentations and management of CSOM related complications.</p><p class="abstract"><strong>Methods:</strong> All patients of chronic supurrative otitis media with intra or extracranial complication who were admitted in Department of Otorhinolaryngology Head and Neck surgery, Sir. T. General Hospital, Government Medical College, Bhavnagar from July 2015 to December 2018 was included in this study. Data of clinical presentation, associated complication, management, and follow-up were analysed. </p><p class="abstract"><strong>Results:</strong> Out of 250 patients of CSOM admitted during these 3 years in ENT Department, 36 patients presented with CSOM related complications. 15 patients presented with intracranial complications and 21 patients presented with extracranial complications.</p><p class="abstract"><strong>Conclusions:</strong> Inspite of availability of higher antibiotics, CSOM related complications are still common. In all the patients require higher intravenous antibiotics (which crosses blood brain barrier) followed by mastoid surgeries.</p>

Neuroprotective effects of resveratrol in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, which is commonly seen in older individuals. This is characterized by cognitive dysfunction, which leads to dementia. Pharmacological treatments for AD are mainly targeted on its symptoms like memory loss and cognitive impairment. The pathophysiology involved in AD is intra-neuronal accumulation of hyper-phosphorylated tau protein as neurofibrillary tangle and extra cellular beta amyloid plaque deposition, which is due to oxidative stress. Here we review the neuro-protective effects of Resveratrol (RSV) and its treatment efficacy in AD. RSV is a naturally available polyphenolic compound, which has antioxidant, anti-cancerous, anti-inflammatory and anti-aging properties. RSV crosses blood brain barrier and exerts its antioxidant effect by enhancing the anti-oxidant enzymes. RSV is involved in Sirtuin (SIRT1) mediated lifespan extension activity. RSV has reduced glial activation and helped in increasing the hippocampal neurogenesis. RSV was able to decrease the expression of amyloid precursor protein, along with improvement of spatial working memory. Since RSV acts as an antioxidant, it can be safely used as oral drug.

CELLULAR MECHANISMS OF NEUROPSYCHIATRIC SYMPTOMS INDUCED BY HYPOTHYROIDISM IN MOUSE MODEL

Thyroid hormones (THs) are essential not only for the development of the central nervous system (CNS) but also for matured brain function. In the CNS, circulating thyroxine (T4) crosses blood-brain barrier via specific transporters and is taken up to astrocytes, becomes L-tri-iodothyronine (3, 3’, 5-triiodothyronine; T3), an active form of TH, by type 2 de-iodinase (D2). T3 is released to the brain parenchyma from astrocytes (glioendocrine system). In adult CNS, both hypo- and hyper-thyroidism, the prevalence in female being > 10 times higher than that in male, may affect psychological condition and potentially increase the risk of cognitive impairment and neurodegeneration including Alzheimer’s disease (AD). We have reported, that non-genomic effects of T3 on microglial functions and its signaling [1] and sex- and age-dependent effects of THs on glial morphology in the mouse brains of hyperthyroidism [2, 3]. Behavioral changes and spine density in hippocampus also showed sex-dependence. Recently we analyzed the opposite thyroid dysfunction, hypothyroidism, and found sex- and age-dependent changes in glial morphology and animal behavior as well. These results may help to understand physiological and/or pathophysiological functions of THs in the CNS and how hyper- and hypothyroidism affect psychological condition and cognition.

Recuperative effect of metformin loaded polydopamine nanoformulation promoting EZH2 mediated proteasomal degradation of phospho-α-synuclein in Parkinson’s disease model

Posttranslational modification and agglomeration of α-synuclein (α-Syn), mitochondrial dysfunction, oxidative stress and loss of dopaminergic neurons are hallmark of Parkinson’s disease (PD). This paper evaluates neuroprotection efficacy of nature inspired biocompatible polydopamine nanocarrier for metformin delivery (Met encapsulated PDANPs) by crossing blood brain barrier in in vitro, 3D and in vivo experimental PD models. The neuroprotective potential was arbitrated by downregulation of phospho-serine 129 (pSer129) α-Syn, with reduction in oxidative stress, prevention of apoptosis and anti-inflammatory activities. The neuroprotective mechanism proved novel interaction of epigenetic regulator EZH2 mediated ubiquitination and proteasomal degradation of aggregated pSer129 α-Syn. In summary, this study divulges the neuroprotective role of Met loaded PDANPs by reversing the neurochemical deficits by confirming an epigenetic mediated nanotherapeutic approach for the PD prevention.

Time to test antibacterial therapy in Alzheimer's disease.

Alzheimer's disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer's disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer's disease and in subjects at risk of developing Alzheimer's disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer's disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer's disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer's disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood-brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood-brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may impact Alzheimer's disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer's disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer's disease. One is that patients with Alzheimer's disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer's disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer's disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer's disease, antibacterial drugs are not being widely investigated in patients with Alzheimer's disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer's disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer's disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer's disease.

Frequency of Brain Metastasis in Breast Cancer Patients and Factors Leading to it

Objective: Breast cancer is the second commonest cause of brain metastasis after lung cancer.10-16% of patients diagnosed with breast cancer ultimately develop brain metastasis. As most of chemotherapeutic drugs do not cross blood brain barrier despite adequate management of breast cancer risk of CNS relapse persist. Prognosis for breast cancer patients after developing brain metastases is poor. Therefore, we sought to determine the frequency of brain metastasis in Pakistani breast cancer survivors, how often brain metastasis is the first site of recurrence and what are the risk factors that indicate greater likelihood of this event occurrence so that more accurate screening for patients at risk can be established. Methods: We retrospectively reviewed medical record of 507 patients with invasive breast cancer of all stages who received treatment in Liaquat National Hospital from January 2010 to December 2015. Patients who developed brain metastasis were identified and stratified according to risk factors. Result: Out of 507 patients 51(10%) developed brain metastasis. 14 patients had brain metastasis as first site of recurrence. On univariate analysis negative hormone receptor status, triple negative and her2 enriched subtype, higher tumor size, lymph node positivity, stages 3 and 4, lymphovascular and peri nodal extension, shorter diseasefree survival and recurrence with visceral metastasis had a statistically highly significant impact on brain metastasis occurrence, while young age at diagnosis (≤35 years), menopausal status, BMI and tumor histology showed no statistically significant impact. Conclusion: Brain metastases are more frequent in triple negative, Her2Neu positive and Estrogen and Progesterone receptor negative patients. Other factors associated with higher risk of brain metastases in breast cancer patients include larger tumor size, positive axillary lymph nodes, higher stage and lymphovascular and periodontal invasion. Frequency of brain metastasis in breast cancer patients and factors leading to it.

Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood–brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

Studies on solvent systems for enhanced skin permeation of venlafaxine hydrochloride

Venlafaxine hydrochloride (VH) is a serotonin-noradrenaline reuptake inhibitor indicated for treatment of depression disorder. It shows low biological half-life 5±2 h and low oral bioavailability 45±15 % due to extensive hepatic first-pass metabolism. Frequent administration of VH is required to maintain steady state plasma concentration of drug. To overcome hepatic first pass metabolism and to cross blood brain barrier for effectively achieving plasma concentration of VH in brain, we envisaged to develop transdermal drug delivery system containing VH loaded polymeric nanoparticles. Effect of solvent systems (SS), penetration enhancers (PE), and VH nanoparticles (VHNPs) on transdermal diffusion of drug were studied. VHNPs were prepared by double emulsion solvent evaporation method using high speed homogenizer followed by probe sonication. Poly (lactic-co-glycolic acid) and tween 80 were used as polymer and surfactant respectively. Mean particle size, polydispersity index, zeta potential, entrapment efficiency of optimized VHNPs were found to be 175.4 nm, 0.109, (-) 24 mV and 56 %.respectively. Scanning electron microscopy confirmed spherical shape of drug loaded polymeric nanoparticles. SS comprising 50% PG in EtOH shown maximum flux 158.67 ± 2.9 (µg/cm2/h) and lag time was found to be 5.60 ±0.16 h. The PE 5 (%v/v) limonene shown maximum flux 200.47±3.6 (µg/cm2/h) and lag time 3.17±0.11 h. The flux and lag time in case of VHNPs were found to be 192.24±3.20 (µg/cm2/h) and 4.22±0.14 h respectively. Based on flux, clearance and surface area of transdermal patch, a theoretical meaningful plasma level concentration of VH ranging from 12.85 to 128.5 (ng/mL) can be achieved.
 Keywords: Depression, Venlafaxine hydrochloride, Poly (lactic-co-glycolic acid), Solvent systems, Penetration enhancers, Nanoparticles (NPs)

A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.

3012 Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50ththe NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( > grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.

Neurological Changes of Adults Residing in Lead Exposed Environment of Myeik Township

Lead crosses blood brain barrier and adversely affects the cognitive function, causing impairment of neuropsychological functions. Most of the lead poisonings are asymptomatic and subclinical cases. A cross-sectional analytical study was designed to assess the neurological changes of adults, aged between 20 to 45 years old, residing in lead exposed environment of Myeik Township. The study focused on the cognitive and psychomotor ability of people who lived in those areas at least one year. A total of 95 subjects were interviewed by using the structured questionnaires for assessment of cognitive and psychomotor ability by well-trained researchers. The mean age of all participants was 32.7±8.5 years. The average duration of stay in these areas was approximately 20 years (maximum duration=47 years). The blood lead level was measured by graphite furnace Atomic Absorption Spectrophotometer. The mean blood lead level of all participants was 19.91±1.8 µg/dl. All the participants were divided into two groups: lower blood lead group (blood lead <10 µg/dl) (n=37) and higher blood lead group (blood lead ≥10 µg/dl) (n=58). The cognitive function was assessed by using three subtests (digit span, visual memory and paired associate learning) from the General Memory Scale. The mean scores were (10.51± 2.0, 5.59±0.5 and 20.01±8.3) in lower blood lead and (9.55±1.8, 5.12±0.7 and 15.23±5.2) in higher lead group, respectively. In addition, the mean total score of cognitive ability test in lower blood lead group was (36.12±9.5) and higher group was (29.90±5.8). All 3 test scores and total scores were significantly lower in higher blood lead group and it could be concluded that the higher the blood lead level, the lower the cognitive ability. To assess psychomotor ability, we used digit symbol, Bourdon-Wiersma vigilance tests and Santa-Ana dexterity test. Among these three tests, the mean scores of Santa-Ana dexterity test (dominant hand) was significantly longer duration (54.40±10.9 vs. 59.46±10.18) in higher blood lead group than in lower blood lead group. All these findings pointed out that lead intoxication would reduce not only cognitive ability but also psychomotor ability

A futuristic perspective in subsiding the symptoms of Parkinson’s Disease

Parkinson's disease (PD) is a neurodegenerative disorder that primarily impinges the dopaminergic neurons in a particular region of Brain termed as Substantia Nigra. The disease affects more than 1900 people per 100,000 aged 80 years and above. Furthermore, men are 1.5 times more prone than their counterpart. Potential biomarkers escalated the precise diagnosis and helped to initiate treatment to limit its adversity. The current therapeutic schemes are focused on administration of Dopamine precursor, Dopamine agonist, Monoamine oxidase (MAO) inhibitor, Catechol-o-methyl transferase (COMT) inhibitors and deep brain stimulation. The CNS delivery focuses mainly on increasing the dopamine level in the brain. CNS drug delivery faces a crucial challenge of crossing Blood Brain Barrier. Blood-Brain Barrier Penetration can be attained by several techniques. Conventional drug therapy yields harmful affects to the patients without much therapeutics. It is visible that crossing BBB is quite strenuous process. It is mandatory for developing a novel approach untangling these situations. Nanotechnology-based formulations like nanosuspensions, nanotubes etc. promotes the penetration of drug across the sophisticated barrier without creating any deterioration to cells or organs. Several novel routes for drug administration reduce dose intake with increased and precise pharmacological action. Nanoformulations and Novel routes of drug administration are a promising tool to enhance the action of drug which helps to abate the symptoms of the Disease and assist in the betterment in treatment.

Perspective in Nuclear Theranostics Using Exosome for the Brain.

Owing to its highly biocompatible property as naturally produced nanoscale particle and drug carrying ability, exosome has attracted much interest in the biomedical area. Versatile functions of exosome in biological system play an important role in elucidating mysterious and unknown biological processes and pathological disease progression. For usage of exosome as brain disease therapeutics, even though the ability of exosomes crossing blood brain barrier (BBB) is not well clearly proven, the small size and their own characteristics possessing cell-derived molecular contents may provide great and beneficial tools for brain delivery and brain-associated disease therapy. A variety of trials related to bioapplications using stem cell-derived exosome in regenerative therapy or autologous exosome shuttling inhibitor targeting brain disease-associated protein marker enhance possibility of exosome toward clinical application. The radionuclide PET or SPECT imaging of radiolabeled exosome will be clearly able to provide accurate clues for analyzing their whole body distribution, targeting efficacy, and the degree of non-specific tissue uptake. In this perspective, the practical information on thranostics of exosome for brain delivery and therapy is offered and radionuclide-based exosome applicability will be dealt with.

ZnO Nanoflower petals mediated amyloid degradation - An in vitro electrokinetic potential approach

An electrokinetic potential (ζ-potential) based approach was introduced to address the amyloid degradation on ZnO-nanoflower platform. The hallmark of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease (PD), Creutzfeldt-Jakob Disease (CJD), Prion- associated diseases, type-II diabetes, etc. is the deposition of misfolded protein aggregates predominantly β-sheeted in structure and fibrillar morphology, known as amyloids, in the brain and different parts of the body. Agents that can degrade these amyloids can be potential candidate for the therapy of amyloidosis. Ultrasmall nanoparticles are gaining interest due to their ability to cross blood brain barrier (BBB) which is favorable for the treatment of neurodegenerative disorders. Considering the influence of Zn2+ in the formation of Aβ aggregates instead of fibrillation, the present study was designed based on the ZnO nanoparticles (ZnO-NP) and ZnO nanoflowers (ZnO-NF) to compare the anti amyloid ability using a model huminsulin amyloid. Fluorescence study, atomic force microscopy (AFM), IR spectroscopy (FTIR) and reduction of fibril size using dynamic light scattering showed that ZnO-NF can degrade amyloids with a higher capacity than their nanoparticle counterpart. Significant reduction in magnitude of ζ-potential in ZnO-NF treated huminsulin amyloid supported the notion to come to the consensus and became the new indicator for anti-amyloidosis. The cell viability assay of ZnO-NP and ZnO-NF at a higher dose than that used for amyloid degradation using PC12 and HaCaT cell lines showed their biocompatibility in a safe manner. Thus, it can be suggested that ZnO-NF would be a better candidate for amyloid degradation compared to ZnO-NPs due to higher surface to volume ratio of the petals.

Blockade of a Laminin-411-Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk.

There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma.Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth.

Asiatic Acid Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress and Apoptosis Via AKT/GSK-3β Signaling Pathway in Wistar Rats.

Asiatic acid (AA), a triterpenoid present in Centella asiatica, possesses the ability to cross blood brain barrier and received considerable attention for its neuroprotective role. We have reported the benefit of AA against aluminum chloride (AlCl3)-induced amyloid pathology, enhanced acetylcholine esterase (AChE) activity, and inflammation in Alzheimer's disease (AD) like model rats. Based on that, to find the exact mechanism of action of AA, the present study was designed to evaluate the oxidative stress, tau pathology, apoptosis, and Akt/GSK3β signaling pathway on AlCl3-induced neurotoxicity in Wistar rats. AD-like pathology was induced by oral administration of AlCl3 (100mg/kg b.w.) for 6weeks, which demonstrated a significant reduction in spatial memory performance, anxiety, and motor dysfunction and diminished the expression of cyclin-dependent kinase 5 (CDK 5-enzyme implicated in the phosphorylation of tau proteins), pTau, oxidative stress, and apoptosis, whereas oral ingestion of AA (75mg/kg b.w.) for 7weeks attenuated the above-said indices, which could be by activating Akt/GSK3β pathway. Current results suggested that AA could be able to modulate various pathological features of AD and could hold promise in AD treatment.