Current Drug Delivery - Volume 14, Issue 6, 2017

Background: Dementia cases are increasing as the population ages, leading to increased financial costs. Several neuronal diseases including ischemic and hemorrhagic stroke involve cerebrovascular injury or pathophysiology. Cerebrovascular injury is closely tied to blood brain barrier (BBB) disruption. Many studies have shown a significant association between BBB dysfunction and neurological diseases. Therefore, an understanding of the molecular mechanisms which regulate BBB permeability and disruption is essential for establishing future therapeutic strategies to alter dementia disease progression related to cerebrovascular injury, so-called vascular cognitive impairment (VCI). microRNAs (miRs) are small non-coding RNAs that regulate gene expression through targeting of mRNA transcripts. miRs have been implicated in the development and progression of various illnesses, including vascular disease. However, the role of miRs in BBB breakdown or permeability and VCI development has not yet been well clarified. Method: Research content related to the origins of VCI and the role of the BBB in pathologic development and therapeutic targeting are reviewed, including current relevant animal models. We draw from the published literature regarding microRNA candidates that are associated with modulation of BBB structure and function. Results: In this review, we summarize the current knowledge about VCI, explore the potential role of miRs in BBB breakdown and VCI progression, and identify potential candidate miRs for development of new treatment strategies. Conclusion: miRs constitute a promising novel avenue as future therapeutic options for alteration of both BBB permeability and development of VCI.

Background: An insult due to intracerebral hemorrhage (ICH) is critical to patients. So, breakthroughs in ICH treatment are very important. Objective: Advances in the stem cell treatment of stroke have been remarkable. And stem cell experimentation on ischemic stroke, however, preceded such work on ICH and did not emphasized ICH therapy. Method: We review recent stem cell treatments for ICH, an experimental model of ICH, the medical care of ICH, and several stem cell therapies for ICH along with future prospects. Results: Stem cell therapy for ICH is effective in rodent or animal models. For humans, only a small number of clinical trials have been done, and significant functional recovery was recorded. Conclusion: We need to reveal the mechanism of stem cell therapy and develop a reliable, definitive treatment strategy for treatment of ICH. In the future, several types of stem cells will be available for the treatment of ICH.

Background: Ischemic stroke is the third leading cause of death and the most frequent cause of permanent disability in adults worldwide. Tremendous advances have been made in understanding of the pathophysiology of cerebral ischemia. Nevertheless, there is still no effective neuroprotectant available in the clinical work. Recently, osteopontin (OPN), a glycophosphoprotein, has attracted more attention due to its various effects in cardiovascular and nervous system diseases. Objective: The aim of present review was to summarize recent findings about neuroprotective effects of OPN on ischemic stroke, targeting to provide a novel therapeutic strategy. Methods: To prepare this review, a pathophysiological and pharmacological literature survey was performed using PubMed, and Web of Science. Also, some statistical and epidemiological literature sources were used. Results: Mounting evidence indicates that OPN attenuates cerebral damage and promotes neurogenesis in ischemic stroke by binding to its receptors to activate diverse signaling pathways. Conclusion: The paper highlights the neuroprotective and pro-regenerative effects of OPN after cerebral ischemia, which would demonstrate its therapeutic potential in ischemic stroke and other informs of ischemic brain injury.

Background: Despite long-standing and worldwide efforts, hemorrhagic stroke remains a critical clinical syndrome that exerts a heavy toll on affected individuals and their families due to the lack of preventive and therapeutic targets. Objective: To clarify the pathogenesis of hemorrhagic stroke and to identify novel therapeutic targets. Method: Targeting pericytes, the typical mural cells of microvessels, could serve as a way to modulate microvascular permeability, development, and maturation by regulating endothelial cell functions and modulating tissue fibrosis and inflammatory responses. Results: Pericytes in hemorrhagic stroke may exert the following functions: before bleeding, the morphological aberration and dysfunction of pericytes may lead to aneurysm formation, angiopsathyrosis, and hemodynamic disturbances, ultimately causing vasculature rupture. In the acute phase after hemorrhage, pericytes are faced with a complicated bleeding environment, which results in the death of pericytes, blood-brain barrier damage, pericyte-mediated inflammatory cascades, white matter impairment, and ultimately aggravated neural injury. In the recovery period post-hemorrhage, in situ pericytes are activated and differentiate into neurons, glia and endothelial cells to repair the neural vascular network. Moreover, many pericytes are recruited to the lesion and contribute to blood-brain barrier remodeling, thus facilitating neurovascular functional recovery after stroke. Conclusion: Due to the multiple functions of pericytes in the development of vascular rupture and hemorrhagic stroke pathophysiology, additional drugs and trials targeting pericytes and evaluations of their effectiveness are required in future investigations to develop new strategies for the prevention and treatment of hemorrhagic stroke.

High mobility group box-1 (HMGB1) is a nuclear protein that is expressed in almost all eukaryotic cells. In the nucleus, it maintains nuclear homeostasis and promotes gene transcription. HMGB1 can be passively released into the extracellular milieu after cell necrosis or actively secreted by activated immune cells. HMGB1 has several receptors such as Toll-like receptor 2, Toll-like receptor 4, and the receptor for advanced glycation end products. After brain injury, HMGB1 is released early from neural cells and contributes to the initial stages of the inflammatory response. However, surprisingly, HMGB1 can mediate beneficial effects during the course of stroke recovery. The biphasic biological property of extracellular HMGB1 may be related to the redox modifications of its cysteine residues. This review discusses the emerging roles of HMGB1 in several stroke models, as well as its potential role as a therapeutic target for stroke patients.

Background: Immune responses including Microglia and macrophage activation and peripheral immune cells infiltration have been founded in the central nervous system (CNS) in recent years. Thus, the traditional view of the adult brain as an immune-privileged organ has been changed. Methods: A systematic literature search was performed using Pubmed and Embase electronic databases without any limitations for a retrospective analysis. Results: The increase a number of studies indicated that the PD-1(programmed cell death-1)/PD-Ls signal pathway played an important role in regulating the immunopathogenesis of brain after injured. The relevant knowledges about PD-1/PD-Ls signal pathway, and potential effect with immune cells, cerebral ischemia, brain tumors and multiple sclerosis were reviewed in this paper. Conclusion: PD-1/PD-Ls played important roles in maintaining immunity balance and the development and prognosis of CNS diseases, but the specific mechanism was still not well understood.

Background: The sestrin family includes several conserved stress-induced proteins that contribute to the maintenance of homeostasis, DNA stability and cell viability in response to various types of injuries. Objective: It is well established that the protective functions of AMP-dependent protein kinase (AMPK) and/or mammalian target of rapamycin (mTOR) are regulated by sestrins. Additionally, it has been revealed that sestrins are able to protect cells from oxidative stress by scavenging reactive oxygen species (ROS). Method: The essential involvement of sestrins in mTORC1 inhibition and ROS scavenging signaling pathways, which modulate metabolism homeostasis and regulate autophagy, indicates that sestrins may serve as a potential agent for cell growth, development, metabolism, and neurodegenerative disorders. However, the potential role of sestrins in stroke has not been discussed and summarized. Results & Conclusion: Based on the current understanding of sestrins, it is believed that sestrins are one of the potential endogenous protective molecules/mechanisms following cerebral stroke, which are associated with neuronal protection, neuroinflammation suppression, and blood brain barrier preservation.

Background: The basal ganglia, an important functional integrity of the brain, comprises multiple subcortical nuclei. The area is mainly supplied by the perforating branches of ipsilateral middle cerebral artery (MCA). The unilateral non-traumatic basal ganglia hemorrhage, commonly located in the putamen, most often results from hypertension. Method: Simultaneous bilateral basal ganglia hemorrhage (SBBGH) is extremely rare. There have been less than 30 case reports worldwide so far. Our article is the first comprehensive review on SBBGH. Conclusion: The clinical features, causes and prognosis were summarized and discussed, in perspective of providing guidance for future diagnosis and treatment.

Background: Stroke is the second leading cause of death worldwide. Understanding of gene expression dynamics could bring new approaches in diagnostics and therapy of stroke. Small noncoding molecules termed “microRNA” represent the most flexible network of gene expression regulators. Method: The aim of this review was to briefly describe the structure and function of microRNA and summarize the current knowledge about the involvement of microRNAs in the pathophysiology of ischemic and hemorrhagic stroke based on both experimental and clinical studies. Results: Numerous profiling studies identified candidate microRNAs and partially described dynamics of their expression after the stroke. However, complex associations of specific microRNAs expression with main clinical characteristics and deeper insight into mechanisms of their regulatory functions are still missing. In this review, we put special emphasis on several microRNA clusters involved in neuroprotection (miR-124, miR-181, miR-21, miR-29, miR-210 and let7). Potential application of microRNAs as biomarkers and diagnostic or therapeutic targets was also discussed. Conclusion: Full understanding of the regulatory mechanisms of the microRNA networks represents a novel direction for stroke research. To date, we do not have effective tools to control pathophysiological processes associated with stroke. Thus the microRNAs have to be considered as a very promising target for future stroke therapies.

Background: Subarachnoid hemorrhage (SAH) is considered as a violent disease with high rate of morbidity and mortality. Early brain injury (EBI) and delayed vasospasm are the two aspects of this disease that are becoming research hotspots. Objective: We aim to update the role of oxidative stress in the development of EBI and delayed cerebral vasospasm after SAH. Method: We reviewed early researches, and mainly discussed three aspects of contents: reactive oxygen species (ROS) production, the role of oxidative stress in early brain injury and delayed vasospasm, and clinical implications. Results: There are several sources for the excessive generation of oxidants after SAH such as disrupted mitochondrial respiration, upregulated enzymatic pathways, extracellular hemoglobin degradation and depressed intrinsic antioxidant systems. Neuron apoptosis induced by ROS is one vital mechanism of EBI. And extracellular hemoglobin degradation and nitric oxide synthases up-reputation are involved in the pathogenesis of delayed cerebral vasospasm. Some antioxidants show significant neuroprotection in researches. Conclusion: ROS production increases in SAH via mitochondria, hemoglobin or enzymatic pathway, and it plays a vital important role in SAH. It seems that antioxidant therapy will be most effective as one component in a treatment regime that attempts to address all the different pathways to EBI and vasospasm following SAH.

Background: Cerebral vasospasm (CVS) is well known as a major complication in subarachnoid hemorrhage (SAH) patients, and research has long been focused on improving morbidity and mortality. As CVS commonly develops from day 4 to day 14 after SAH onset, SAH patients require therapies with drugs for preventing CVS after surgical treatment for the source of hemorrhage, mostly ruptured intracranial aneurysms. It is thought that the pathogenesis of CVS is initiated by prolonged smooth muscle contraction, and the subsequent hypoperfusion and cytotoxic responses induce cerebral ischemia. Although therapeutic investigations have historically focused on morphological improvement, the improvement of outcome is limited by the reversal of arterial narrowing. Therefore, it might be important to look back at evidence from long-lasting studies of CVS and to determine a highroad to effective drugs, including combination therapy. Objective: In this review, we introduce current candidate beneficial drugs against CVS in clinical SAH, including nimodipine and other Ca2+ channel antagonists, magnesium sulfate, clazosentan, statins, cilostazol, eicosapentaenoic acid, fasudil hydrochloride, milrinone, and edaravone, all of which have been frequently studied in recent years.

Objective: Erythropoietin (EPO) for treating acute ischemic stroke (AIS) has been investigated in many studies. However, the evidence was inconsistent. Thus, a systematic review and metaanalysis were performed to elucidate the role of EPO in treating patients with AIS. Methods: Two electronic databases (PubMed and EMBASE) were used. 30-day NIHSS measures primary outcome while all-cause mortality in the follow up and 90-day Barthel Index were regarded as secondary outcome. Results are presented as relative risk (RR), standardized mean difference (SMD) and 95% confidence intervals (CI). We employed Stata software to perform the meta-analysis. Results: Four randomized controlled trials (RCTs) involving 784 patients were contained in this metaanalysis. The total combined results on 30-day NIHSS were (SMD = -0.52, 95% CI: -1.39, 0.34) with random-effects model and sensitivity analysis showed a significant difference after excluding the Ehrenreich 2009 trial. The total combined secondary measured results were (RR=1.72, 95% CI: 1.10, 2.70) and (SMD = 0.01, 95% CI: -0.14, 0.16) for all-cause mortality and 90-day Barthel Index. In the subgroup analysis by using recombinant tissue plasminogen activator (rtPA) earlier, the rtPA group showed increased all-cause mortality with the result of (RR = 1.92, 95% CI: 1.04, 3.52), but not in non-rtPA group. Conclusion: To our systematic review and meta-analysis, we didn’t recommend EPO administration for patients with AIS, especially with the combination of rtPA. Large RCTs are warranted to examine EPO efficacy in AIS patients in the future.

Background: Although sphingosine 1-phosphate (S1P) receptor activation by FTY720 (fingolimod) has been suggested to improve the prognosis of experimental stroke, the effect of the drug in early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the precise mechanism of the effect are undetermined. In this study, we investigated the protective effect of systemic administration of FTY720 in EBI after SAH and assessed the mechanism using intracerebroventricular infusion of VPC23019 which is the S1P receptor antagonist. Method: SAH rats were produced by the endovascular perforation model and injected saline or 1mg/kg FTY720 intraperitoneally at 30 minutes after SAH induction. Neurological function, cerebral blood flow, amount of subarachnoid blood, and brain edema were evaluated to confirm the protective effect of systemic administration of FTY720. SAH rats also received VPC23019 intraventricularly before SAH induction to abolish the central S1P receptor activation. Results: Systemic administration of FTY720 significantly ameliorated SAH-induced neurological deficits and brain edema without modulation of CBF and the amount of subarachnoid blood. Blockage of central S1P receptor with VPC23019 did not abolish the protective effects of FTY720. Conclusion: The present study suggests that systemic administration of FTY720 reduces EBI after SAH and that the effect might not come from central S1P activation but be associated with pleiotropic actions of the drug.

Background: Nasal delivery of 20 (R) -ginsenoside Rg3 (Rg3) has a short-lived anti-fatigue effect owing to rapid clearance by nasal cilia. Thus, in order to extend the residence time of Rg3 in the nasal cavity, a new drug delivery system is needed. Methods: Chitosan microspheres loaded with Rg3 were prepared using a multi-step emulsification method and were characterized in vitro and in vivo. Results: The microspheres had a spherical shape with a mean diameter of 44.9±12.6 08m. The drugloading ratio was 10.25±0.08%, and the encapsulation ratio was 30.61±1.46%. Our in vitro mucoadhesion experiment demonstrated that 70.35±1.79% of the microspheres adhered to the nasal mucosa. The in vitro release study revealed that 31.1% of the Rg3 was released from the microspheres in the first 10 min. Release slowed, with 88.64% of the Rg3 released within 6 h. The pharmacodynamics study demonstrated that the weight-bearing swimming time of mice increased significantly from 432±89 s to 486±96 s after administration of Rg3 microspheres compared with the Rg3 water solution. Blood lactic acid and serum urea nitrogen significantly decreased in the group administered microspheres compared to the water solution group (p<0.05). Hepatic glycogen and lactate dehydrogenase increased significantly in the group administered microspheres compared to the water solution group (p<0.01). Conclusion: 20 (R) -ginsenoside Rg3 entrapped in chitosan microspheres may have a beneficial effect against fatigue by increasing the residence time of Rg3 in the nasal cavity and enhancing absorption by the nasal mucosa.

Background: Curcumin, a natural hydrophobic polyphenol, has been reported to have diverse pharmacological activities. Previous studies have evaluated its efficacy using both oral and transdermal dosage forms. However, two major obstacles-poor aqueous solubility and low stability-severely limited its pharmaceutical use. Objective: The main objective of this study was to prepare curcumin eye drops that provided sustained release to allow for once daily application in retinitis pigmentosa. Method: To achieve our goal, curcumin was complexed with β -cyclodextrin and hydroxypropyl-β- cyclodextrin in two molar ratios (1:1 and 1:2) using co-solvent, co-solvent with sonication and freezedrying filtration methods. A total of 12 complexes were prepared, then characterized using differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, solubility assessment and in vitro release studies. Results: An improvement in curcumin aqueous solubility relative to pure curcumin was achieved for all 12 complexes. However, the freeze-drying filtration method was superior to all other methods because it produced highly water-soluble drug-CD complexes. Based on our stability analyses, pH 6.8 phosphate buffer containing 1% Tween 80 was selected as the release medium for in vitro release studies because curcumin exhibited high stability in this medium. Our F11 formulation provided sustained release of the drug for more than 96 h with a maximum amount released of drug (21.77±0.26 μg/ml). Our in vitro release data also showed that release of drug from curcumin-CDs inclusion complexes followed a Higuchi non-Fickian diffusion mechanism. Conclusion: Based on these results, F11 was formulated as eye drops, which provide a promising once daily novel topical delivery of this naturally derived phytochemical.

Background: Capecitabine, an anti cancer drug, has a very short drug elimination half-life (0.49 to 0.89 h). High doses and absence of targeting ability in the colon region may lead to more side effects to the patients with colon cancer. Purpose: To develop and optimize sustained release nanoparticles for effective treatment of colon cancer. Methods: Eudragit S100-PLGA(poly (lactic-co-glycolic acid)) nanoparticles were prepared by a double emulsification, solvent evaporation method followed by high-pressure homogenisation evaluated and the particles were evaluated for surface morphology, particle size analysis, polydispersity index, drug content, % entrapment efficiency and in vitro drug release. To optimize the batch a 32 full factorial design was applied. The optimized batch was evaluated for cytotoxicity and cellular uptake study. Results and Discussion: The optimized formulation exhibited 179.25 nm mean particle size, 71.27% of drug entrapment efficiency and 81.824% drug release up to 72 h. When the concentration of capecitabine was increased from 50-500 μg/ml, the % cytotoxicity of nanoparticles and capecitabine (pure drug) increased from 8.5 to 97.70% and 2.7 to 82.23%, respectively. As per a cellular uptake study, the optimized nanoparticles were completely uptaken by HT 29 adenocarcinoma cells within 2 to 4 h. Conclusion: Optimized Eudragit S100-PLGA nanoparticles are a promising delivery system for colon targeting.