Monocyte chemotactic protein-1 as a potential biomarker for early anti-thrombotic therapy after ischemic stroke

Inflammation following ischemic brain injury is correlated with adverse outcome. Preclinical studies indicate that treatment with acetylsalicylic acid + extended-release dipyridamole (ASA + ER-DP) has anti-inflammatory and thereby neuroprotective effects by inhibition of monocyte chemotactic protein-1 (MCP-1) expression. We hypothesized that early treatment with ASA + ER-DP will reduce levels of MCP-1 also in patients with ischemic stroke. The EARLY trial randomized patients with ischemic stroke or TIA to either ASA + ER-DP treatment or ASA monotherapy within 24 h following the event. After 7 days, all patients were treated for up to 90 days with ASA + ER-DP. MCP-1 was determined from blood samples taken from 425 patients on admission and day 8. The change in MCP-1 from admission to day 8 did not differ between patients treated with ASA + ER-DP and ASA monotherapy (p > 0.05). Comparisons within MCP-1 baseline quartiles indicated that patients in the highest quartile (>217-973 pg/mL) showed improved outcome at 90 days if treated with ASA + ER-DP in comparison to treatment with ASA alone (p = 0.004). Our data does not provide any evidence that treatment with ASA + ER-DP lowers MCP-1 in acute stroke patients. However, MCP-1 may be a useful biomarker for deciding on early stroke therapy, as patients with high MCP-1 at baseline appear to benefit from early treatment with ASA + ER-DP.     

Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia

Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks’ gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2.     

Quest for Quality in Translational Stroke Research—A New Dawn for Neuroprotection?

Despite tremendous progress in modern-day stroke therapy, ischemic stroke remains a disease associated with a high socioeconomic burden in industrialized countries. In light of demographic change, these health care costs are expected to increase even further. The current causal therapeutic treatment paradigms focus on successful thrombolysis or thrombectomy, but only a fraction of patients qualify for these recanalization therapies because of therapeutic time window restrictions or contraindications. Hence, adjuvant therapeutic concepts such as neuroprotection are urgently needed. A bench-to-bedside transfer of neuroprotective approaches under stroke conditions, however, has not been established after more than twenty years of research, albeit a great many data have demonstrated several neuroprotective drugs to be effective in preclinical stroke settings. Prominent examples of substances supported by extensive preclinical evidence but which failed clinical trials are tirilazad and disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059). The NXY-059 trial, for instance, was retrospectively shown to have a seriously weak study design, a trial of insufficient quality and a poor statistical analysis, although it initially met the recommendations of the STAIR committee. In light of currently ongoing novel neuroprotective stroke trials, such as ESCAPE-NA, and to avoid the mistakes made in the past, an improvement in study quality in the field of stroke neuroprotection is urgently needed. In the present review, animal models closely reflecting the “typical” stroke patient, occlusion techniques and the appropriate choice of time windows are discussed. In this context, the STAIR recommendations could provide a useful orientation. Taking all of this into account, a new dawn for neuroprotection might be possible.     

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets

Stroke is among the leading causes of death and disability worldwide. However, despite long-term research yielding numerous candidate neuroprotective drugs, there remains a lack of effective neuroprotective therapies for ischemic stroke patients. Among the factors contributing to this deficiency could be that single-target therapy is insufficient in addressing the complex and extensive mechanistic basis of ischemic brain injury. In this context, lipids serve as an essential component of multiple biological processes and play important roles in the pathogenesis of numerous common neurological diseases. Moreover, in recent years, fatty acid-binding proteins (FABPs), a family of lipid chaperone proteins, have been discovered to be involved in the onset or development of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. However, comparatively little attention has focused on the roles played by FABPs in ischemic stroke. We have recently demonstrated that neural tissue-associated FABPs are involved in the pathological mechanism of ischemic brain injury in mice. Here, we review the literature published in the past decade that has reported on the associations between FABPs and ischemia and summarize the relevant regulatory mechanisms of FABPs implicated in ischemic injury. We also propose candidate FABPs that could serve as potential therapeutic targets for ischemic stroke.     

The Importance of Platelets Response during Antiplatelet Treatment after Ischemic Stroke—Between Benefit and Risk: A Systematic Review

Ischemic stroke is a disease related to abnormal blood flow that leads to brain dysfunction. The early and late phases of the disease are distinguished. A distinction is made between the early and late stages of the disease, and the best effect in treating an ischemic stroke is usually achieved within the first hours after the onset of symptoms. This review looked at studies platelet activity monitoring studies to determine the risks and benefits of various approaches including antiplatelet therapy. A study was conducted on recently published literature based on PRISMA. This review includes 32 research articles directly addressing the importance of monitoring platelet function during antiplatelet therapy (dual or monotherapy) after ischemic stroke. In patients with transient ischemic attack or ischemic stroke, antiplatelet therapy can reduce the risk of stroke by 11–15%, assuming that patients respond well. Secondary prevention results are dependent on platelet reactivity, meaning that patients do not respond equally to antiplatelet therapy. It is very important that aspirin-resistant patients can benefit from the use of dual antiplatelet therapy. The individualized approach to secondary stroke prevention is to administer the most appropriate drug at the correct dose and apply the optimal therapeutic procedure to the individual patient.     

Molecular Biology of Atherosclerotic Ischemic Strokes

Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain ischemia (~80%) or intracranial hemorrhage (~20%). The most common site when ischemia occurs is the one is perfused by middle cerebral arteries. Worse prognosis and disablement consequent to brain damage occur in elderly patients or affected by neurological impairment, hypertension, dyslipidemia, and diabetes. Since, in the coming years, estimates predict an exponential increase of people who have diabetes, the disease mentioned above constitutes together with stroke a severe social and economic burden. In diabetic patients after an ischemic stroke, an exorbitant activation of inflammatory molecular pathways and ongoing inflammation is responsible for more severe brain injury and impairment, promoting the advancement of ischemic stroke and diabetes. Considering that the ominous prognosis of ischemic brain damage could by partially clarified by way of already known risk factors the auspice would be modifying poor outcome in the post-stroke phase detecting novel biomolecules associated with poor prognosis and targeting them for revolutionary therapeutic strategies.     

From Kidney Protection to Stroke Prevention: The Potential Role of Sodium Glucose Cotransporter-2 Inhibitors

Chronic kidney disease (CKD) is an independent risk factor for stroke and covert cerebrovascular disease, and up to 40% of stroke patients have concomitant CKD. However, the so-called “cerebrorenal interaction” attracted less attention compared to its cardiorenal counterpart. Diabetes is the leading cause of CKD. The sodium–glucose cotransporter (SGLT) 2 inhibitor is a relatively new class of oral anti-diabetic drugs and has cardiorenal benefits in addition to glucose-lowering effects. In the present perspective, we would like to review the current status and future potential of the SGLT2 inhibitor in cerebro–renal interactions and strokes regardless of the status of diabetes. We propose the potential roles of baseline renal functions and SGLT1/2 dual inhibition in stroke prevention, as well as the additional benefits of reducing atrial fibrillation and hemorrhagic stroke for SGLT2 inhibitors. Further clinical trials are anticipated to test whether SGLT2 inhibitors can fulfill the long-standing unmet clinical need and stop such a vicious cycle of cerebro–renal interaction.     

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.     

The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent recurrent myocardial infarction and other thrombotic events based on its ability to selectively inhibit thromboxane synthesis without affecting prostacyclin synthesis. With the discovery that thromboxane was increased in preeclamptic women, it was reasonable to evaluate whether low-dose aspirin would be effective for preeclampsia prevention. The first clinical trials were very promising, but then two large multi-center trials dampened enthusiasm until meta-analysis studies showed aspirin was effective, but with caveats. Low-dose aspirin was most effective when started <16 weeks of gestation and at doses >100 mg/day. It was effective in reducing preterm preeclampsia, but not term preeclampsia, and patient compliance and patient weight were important variables. Despite the effectiveness of low-dose aspirin therapy in correcting the placental imbalance between thromboxane and prostacyclin and reducing oxidative stress, some aspirin-treated women still develop preeclampsia. Alterations in placental sphingolipids and hydroxyeicosatetraenoic acids not affected by aspirin, but with biologic actions that could cause preeclampsia, may explain treatment failures. Consideration should be given to aspirin’s effect on neutrophils and pregnancy-specific expression of protease-activated receptor 1, as well as additional mechanisms of action to prevent preeclampsia.     

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4⁺ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A₂ were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.     

Molecular Characterization of Plasma HDL,LDL, and VLDL Lipids Cargos from Atherosclerotic Patients with Advanced Carotid Lesions: A Preliminary Report

Carotid atherosclerosis represents a relevant healthcare problem, since unstable plaques are responsible for approximately 15% of neurologic events, namely transient ischemic attack and stroke. Although statins treatment has proven effective in reducing LDL-cholesterol and the onset of acute clinical events, a residual risk may persist suggesting the need for the detection of reliable molecular markers useful for the identification of patients at higher risk regardless of optimal medical therapy. In this regard, several lines of evidence show a relationship among specific biologically active plasma lipids, atherosclerosis, and acute clinical events. We performed a Selected Reaction Monitoring-based High Performance Liquid Chromatography-tandem Mass Spectrometry (SRM-based HPLC-MS/MS) analysis on plasma HDL, LDL, and VLDL fractions purified, by isopycnic salt gradient ultracentrifugation, from twenty-eight patients undergoing carotid endarterectomy, having either a “hard” or a “soft” plaque, with the aim of characterizing the specific lipidomic patterns associated with features of carotid plaque instability. One hundred and thirty lipid species encompassing different lipid (sub)classes were monitored. Supervised multivariate analysis showed that lipids belonging to phosphatidylethanolamine (PE), sphingomyelin (SM), and diacylglycerol (DG) classes mostly contribute to discrimination within each lipoprotein fraction according to the plaque typology. Differential analysis evidenced a significant dysregulation of LDL PE (38:6), SM (32:1), and SM (32:2) between the two groups of patients (adj. p-value threshold = 0.05 and log₂FC ≥ |0.58|). Using this approach, some LDL-associated markers of plaque vulnerability have been identified, in line with the current knowledge of the key roles of these phospholipids in lipoprotein metabolism and cardiovascular disease. This proof-of-concept study reports promising results, showing that lipoprotein lipidomics may present a valuable approach for identifying new biomarkers of potential clinical relevance.     

Cellular and Molecular Targets for Non-Invasive,Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

BACKGROUND: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. OBJECTIVES: Accumulating data suggest that “non-pharmacological” approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. METHODS: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). RESULTS: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. DISCUSSION: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. CONCLUSIONS: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological.     

Association of the MicroRNA-146a SNP rs2910164 with Ischemic Stroke Incidence and Prognosis in a Chinese Population

We conducted a case-control study investigating the association between the single-nucleotide polymorphism rs2910164 in microRNA (miR)-146a and the risk and prognosis of stroke. We recruited a total of 1139 ischemic stroke patients and 1585 sex- and age-matched control subjects. After a median follow-up period of 4.5 years, 1071 of these ischemic stroke patients were then recruited for a prospective study. Our study revealed that rs2910164 was not associated with ischemic stroke incidence (odds ratio = 1.00; 95% confidence interval (CI) = 0.80–1.24; p = 0.985) by multivariate logistic regression. Meta-analysis of our case-control study and three others on Asian populations also suggested that there was no relationship between rs2910164 and ischemic stroke incidence. The significance of differences in long-term outcomes was examined by the log-rank test of the respective comparison groups. The prospective study showed that rs2910164 led to a 1.56-fold increased risk of stroke recurrence (hazard ratio (HR) = 1.56; 95% CI = 1.10–2.20; p = 0.013) and a 2.13-fold increased risk of death caused by cardiovascular disease or stroke (Csdeath) (HR = 2.13; 95% CI = 1.31–3.46; p = 0.002). The independent association of rs2910164 with stroke prognosis was evaluated using Cox regression models. Therefore, rs2910164 appears to be a strong predictor of stroke prognosis but not of stroke incidence in Asian populations.     

Increased Expression of Interferon-Induced Transmembrane 3 (IFITM3) in Stroke and Other Inflammatory Conditions in the Brain

Microglia, the resident innate immune cells of the brain, become more highly reactive with aging and diseased conditions. In collaboration with other cell types in brains, microglia can contribute both to worsened outcome following stroke or other neurodegenerative diseases and to the recovery process by changing their phenotype toward reparative microglia. Recently, IFITM3 (a member of the “interferon-inducible transmembrane” family) has been revealed as a molecular mediator between amyloid pathology and neuroinflammation. Expression of IFITM3 in glial cells, especially microglia following stroke, is not well described. Here, we present evidence that ischemic stroke causes an increase in IFITM3 expression along with increased microglial activation marker genes in aged brains. To further validate the induction of IFITM3 in post-stroke brains, primary microglia and microglial-like cells were exposed to a variety of inflammatory conditions, which significantly induced IFITM3 as well as other inflammatory markers. These findings suggest the critical role of IFITM3 in inducing inflammation. Our findings on the expression of IFITM3 in microglia and in aged brains following stroke could establish the basic foundations for the role of IFITM3 in a variety of neurodegenerative diseases, particularly those that are prevalent or enhanced in the aged brain.     

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in “high-risk” patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient’s risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.     

Depletion of Arg1-Positive Microglia/Macrophages Exacerbates Cerebral Ischemic Damage by Facilitating the Inflammatory Response

Stroke is a serious worldwide disease that causes death and disability, more than 80% of which is ischemic stroke. The expression of arginase 1 (Arg1), a key player in regulating nitrogen homeostasis, is altered in the peripheral circulation after stroke. Growing evidence indicates that ischemic stroke also induces upregulated Arg1 expression in the central nervous system, especially in activated microglia and macrophages. This implies that Arg1 may affect stroke progression by modulating the cerebral immune response. To investigate the effect of Arg1⁺ microglia/macrophages on ischemic stroke, we selectively eliminated cerebral Arg1⁺ microglia/macrophages by mannosylated clodronate liposomes (MCLs) and investigated their effects on behavior, neurological deficits, and inflammatory responses in mice after ischemic stroke. More than half of Arg1⁺ cells, mainly Arg1⁺ microglia/macrophages, were depleted after MCLs administration, resulting in a significant deterioration of motility in mice. After the elimination of Arg1⁺ microglia/macrophages, the infarct volume expanded and neuronal degenerative lesions intensified. Meanwhile, the absence of Arg1⁺ microglia/macrophages significantly increased the production of pro-inflammatory cytokines and suppressed the expression of anti-inflammatory factors, thus profoundly altering the immune microenvironment at the lesion site. Taken together, our data demonstrate that depletion of Arg1⁺ microglia/macrophages exacerbates neuronal damage by facilitating the inflammatory response, leading to more severe ischemic injury. These results suggest that Arg1⁺ microglia/macrophages, as a subpopulation regulating inflammation, is beneficial in controlling the development of ischemia and promoting recovery from injury. Regulation of Arg1 expression on microglia/macrophages at the right time may be a potential target for the treatment of ischemic brain injury.     

Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.     

Exudative versus Nonexudative Age-Related Macular Degeneration: Physiopathology and Treatment Options

Age-related macular degeneration (AMD) is an eye disease typically associated with the aging and can be classified into two types—namely, the exudative and the nonexudative AMD. Currently available treatments for exudative AMD use intravitreal injections, which are associated with high risk of infection that can lead to endophthalmitis, while no successful treatments yet exist for the nonexudative form of AMD. In addition to the pharmacologic therapies administered by intravitreal injection already approved by the Food and Drug Administration (FDA) in exudative AMD, there are some laser treatments approved that can be used in combination with the pharmacological therapies. In this review, we discuss the latest developments of treatment options for AMD. Relevant literature available from 1993 was used, which included original articles and reviews available in PubMed database and also information collected from Clinical Trials Gov website using “age-related macular degeneration” and “antiangiogenic therapies” as keywords. The clinical trials search was limited to ongoing trials from 2015 to date.