Marci G. Crowley

Utilizing Delta Opioid Receptors and Peptides for Cytoprotection: Implications in Stroke and Other Neurological Disorders

The opioid system has been elucidated as a potential target for therapy in a variety of neurological disorders including stroke. Delta opioid receptors have been revealed to pose an especially compelling biological function for new neuroprotective therapies. Two distinct therapeutic mechanisms have been characterized for delta opioid receptors, namely, these receptors aid in maintaining ionic homeostasis and initiate endogenous neuroprotective pathways. Specific agonists of delta opioid receptors, such as (D-Ala2, D-Leu5) enkephalin (DADLE), have displayed the ability to promote neuronal survival and mitigate apoptotic pathways. These findings have led to a significant amount of research on this molecules potential as a neurotherapeutic. At the forefront of these efforts has been investigation into DADLEs ability to protect neurons and glial cells following ischemia. Additionally, current research is attempting to reveal the dynamic neuroprotective mechanisms that mediate DADLEs therapeutic benefits. This review article discusses the scientific evidence supporting the use of delta opioid family of receptors and ligands as a promising target for therapeutic intervention in neurological disorders, with emphasis on stroke.

Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke

Stem cell therapies have been demonstrated in the laboratory as an effective option in treating a number of neurological disorders, including stroke. By targeting the subacute and chronic phases of stroke, stem cell therapies offer the advantage of extending the intervention window which has traditionally been oppressively small. Although substantial laboratory data support this therapeutic potential, transitioning stem cell treatments into approved clinical products has proven difficult. The reasons for this are many, including fundamental complications which have accompanied non-traditional pharmaceuticals such as difficulties in achieving treatment/dosing/ cell type consensus and also the regulatory and legislative hindrances which have plagued stem cell advancement. Fortunately, translational lab-to-clinic research endeavors are being made in all of the abovementioned categories, allowing the initiation of limited clinical trials of stem cell therapies for stroke patients. Our understanding of stem cell types and their varying sources has been instrumental in furthering the field. Specifically, investigations revealing the bioavailability and stemness capacity of different adult tissue sources—including bone marrow-derived, blood-derived, and adipose-derived— have guided current research efforts. These cell types have circumvented the need for fetal and embryonic stem cells, thus allowing the field to avoid some of the ethical and logistical obstacles which have severely delayed research in the past. Additionally, a rising awareness of the importance of basic science-inspired clinical trial designs has been and will continue to be crucial in the development of successful trials. To date, multiple clinical trials examining the efficacy of stem cell therapies in stroke are currently under way. These clinical trials have reliably displayed the safety of finely regulated stem cell therapies, yet demonstrating their efficacy has proved less consistent—in large part due to small patient enrolment. This lack of demonstration of efficacy in stroke patients (and patients with other neurologic disorders) has left an unmet demand for stem cell therapies. Unregulated and experimental stem cell clinics have risen to fill this demand as a result of the delayed transition from the laboratory to the clinic and the Bcure-all^ promise of stem cells which has been circulated by the media. These scrupulous stem cell clinics operate under minimal oversight in many instances and pose a danger to patients, as well as the stem cell field as a whole. This article will discuss the current state of stem cell research and clinical trials before addressing the dangers which unregulated stem cell therapies present. Finally, practical solutions will be presented for the challenges which are hindering the advancement of stem cell therapies into the clinic for patients suffering from stroke.

Utilizing pharmacotherapy and mesenchymal stem cell therapy to reduce inflammation following traumatic brain injury

The pathologic process of chronic phase traumatic brain injury is associated with spreading inflammation, cell death, and neural dysfunction. It is thought that sequestration of inflammatory mediators can facilitate recovery and promote an environment that fosters cellular regeneration. Studies have targeted post-traumatic brain injury inflammation with the use of pharmacotherapy and cell therapy. These therapeutic options are aimed at reducing the edematous and neurodegenerative inflammation that have been associated with compromising the integrity of the blood-brain barrier. Although studies have yielded positive results from anti-inflammatory pharmacotherapy and cell therapy individually, emerging research has begun to target inflammation using combination therapy. The joint use of anti-inflammatory drugs alongside stem cell transplantation may provide better clinical outcomes for traumatic brain injury patients. Despite the promising results in this field of research, it is important to note that most of the studies mentioned in this review have completed their studies using animal models. Translation of this research into a clinical setting will require additional laboratory experiments and larger preclinical trials.

Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders

Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinsons Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways. Delta opioid agonists such as (D-Ala2, D-Leu5) enkephalin (DADLE) have been shown to promote neuronal survival and decrease apoptosis, resulting in a substantial amount of research for its application as a neurological therapeutic. Most notably, DADLE has demonstrated significant potential to reduce cell death following ischemic events. Current research is working to reveal the complex mechanisms of DADLEs neuroprotective properties. Ultimately, our knowledge of the DOR receptors and agonists has made the opioid system a promising target for therapeutic intervention in many neurological disorders.

Multifaceted Effects of Delta Opioid Receptors and DADLE in Diseases of the Nervous System

BACKGROUND The opioid system is considered a potential therapeutic target in a variety of neurological disorders. Delta opioid receptors (DORs) are broadly expressed in the brain, and their activation protects cells from hypoxic/ischemic insults by counteracting disruptions of ionic homeostasis and initiating neuroprotective pathways. The DOR agonist D-Ala2-D-Leu2-Enkephalin (DADLE) promotes neuronal survival, mitigates apoptotic pathways, and protects neurons and glial cells from ischemia-induced cell death, thus making DADLE a promising therapeutic option for stroke. The significant amount of research regarding DORs and DADLE in the last decades also suggests their potential in treating other neurological disorders. METHODS This review compiled relevant literature detailing the role of DORs and agonists in central nervous system function and neuropathologies. RESULTS Several studies demonstrate potential mechanisms implicating a key interaction between DORs and DADLE in conferring neuroprotective benefits. A better understanding of DOR function in disease-specific contexts is critical to transitioning DOR agonists into the clinic as a therapy for stroke and other neurological diseases. CONCLUSION Evidence-based studies support the potential of the delta-opioid family of receptors and its ligands in developing novel therapeutic strategies for stroke and other brain disorders.

Stem Cell-Paved Biobridge: A Merger of Exogenous and Endogenous Stem Cells Toward Regenerative Medicine in Stroke

Stroke is a significant unmet clinical need with therapeutic options limited to tissue-type plasminogen activator (tPA), which has a small therapeutic window and risk for hemorrhagic transformation. Stroke is a multiphasic disease with a complex pathology. After the initial insult, a cascade of events occur causing secondary cell death and the expansion of the penumbra. The major contributing factors to this secondary cell death are depletion of growth factors, neuroinflammation, and disruption of the neurovascular unit. There is a need for more innovative and effective therapies that can target the diverse pathological consequences of stroke. To this end, stem cell therapy is a promising approach for stroke. Pre-clinical studies have demonstrated the potential of stem cells for treating neurological disorders, including stroke. Here, we discuss diverse stem cell types which have generated encouraging results for advancing to the clinic. Then, we examine the mechanisms of action of stem cells—cell replacement, by stander effect, and a novel biobridge concept advanced by our laboratory. These mechanisms work in concert to afford the neuroprotection and neuroregeneration after stroke. We envision that an in-depth understanding of the benefits and drawbacks of various stem cells and their mechanisms of action will guide the translational entry of stem cell therapy from the laboratory into the clinical setting.

Stem Cell Therapy for Neurovascular and Traumatic Brain Diseases

Diseases of the neurovascular unit, consisting of the endothelial vasculature and supporting cells, are incredibly prevalent in patients. Two such diseases, stroke and traumatic brain injury (TBI), share major pathological similarities, with acute and chronic pathways leading to neurodegeneration. In particular, the neuroinflammatory aspect of stroke and TBI pathology has been shown to contribute significantly to worsening outcomes. Fortunately, neuroinflammation also offers an accessible therapeutic target. Minimal treatment options currently exist for either disease, but stem cell-based therapies have demonstrated great promise in offering neuroprotection and encouraging neuroregeneration after the initial insult. Stem cells have been shown to mitigate chronic neuroinflammation as well as modulate peripheral inflammation via the spleen. Additionally, stem cells have been demonstrated to preferentially migrate to the spleen when injected after a neurovascular injury. This further validates the notion that stem cells are inflammation-honing “biologics” and confer their neuroprotection in large by ameliorating the global inflammatory response. Current research investigations are focused on understanding these cell death and neural repair processes in an effort to utilize the preclinical findings toward efficient strategies designed to employ stem cell therapies as a treatment for stroke, TBI, and other neurovascular diseases. Here, we provide scientific evidence supporting the use of stem cell therapy for neurovascular diseases through the cells’ robust ability to sequester the inflammatory response associated with the secondary cell death that plagues both stroke and TBI.