Poornima Venkat

Models and mechanisms of vascular dementia.

Vascular dementia (VaD) is the second leading form of dementia after Alzheimers disease (AD) plaguing the elderly population. VaD is a progressive disease caused by reduced blood flow to the brain, and it affects cognitive abilities especially executive functioning. VaD is poorly understood and lacks suitable animal models, which constrain the progress on understanding the basis of the disease and developing treatments. This review article discusses VaD, its risk factors, induced cognitive disability, various animal (rodent) models of VaD, pathology, and mechanisms of VaD and treatment options.

New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain.

The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases.

Cell-based and pharmacological neurorestorative therapies for ischemic stroke

ABSTRACT Ischemic stroke remains one of most common causes of death and disability worldwide. Stroke triggers a cascade of events leading to rapid neuronal damage and death. Neuroprotective agents that showed promise in preclinical experiments have failed to translate to the clinic. Even after decades of research, tPA remains the only FDA approved drug for stroke treatment. However, tPA is effective when administered 3–4.5 h after stroke onset and the vast majority of stroke patients do not receive tPA therapy. Therefore, there is a pressing need for novel therapies for ischemic stroke. Since stroke induces rapid cell damage and death, neuroprotective strategies that aim to salvage or replace injured brain tissue are challenged by treatment time frames. To overcome the barriers of neuroprotective therapies, there is an increasing focus on neurorestorative therapies for stroke. In this review article, we provide an update on neurorestorative treatments for stroke using cell therapy such as bone marrow derived mesenchymal stromal cells (BMSCs), human umbilical cord blood cells (HUCBCs) and select pharmacological approaches including Minocycline and Candesartan that have been employed in clinical trials. This review article discusses the present understanding of mechanisms of neurorestorative therapies and summarizes ongoing clinical trials. This article is part of the Special Issue entitled ‘Cerebral Ischemia’. HighlightsCell therapy for stroke has a wide treatment window of days to weeks after stroke.Cell therapy for stroke improves stroke outcome and neurological function.Neurorestorative agents promote neurovascular and white matter remodeling.Minocycline and Candesartan promote neuroprotection and neurorestoration after stroke.

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

Stroke is a major cause of death and long‐term disability accompanied by steep social and medical costs. Diabetes mellitus (DM) is a chronic, lifelong, severe metabolic health problem characterized by hyperglycemia, attributable to insulin deficiency, insulin resistance, or a combination of both.

Cell-Based and Exosome Therapy in Diabetic Stroke

Stroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long‐term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell‐based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cells signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. Stem Cells Translational Medicine 2018;7:451–455

Mesenchymal Stromal Cell Therapy of Stroke

Stroke is a major cause of high mortality, morbidity and long-term disability worldwide. Development of neuroprotective and neurorestorative therapies for stroke has been a target of intense research. Accumulating preclinical literature has identified that bone marrow mesenchymal stromal cell (MSC) treatment of stroke improves neurological functional outcome after stroke. This chapter focuses on the therapeutic effects and molecular mechanisms underlying MSC treatment of stroke, such as angiogenesis, arteriogenesis, neurogenesis and white matter remodeling, as well as a discussion on the interaction/coupling among these restorative events. In addition, the role of microRNAs (miRNAs) and MSC secreted exosomes in mediating intercellular communication between MSCs and parenchymal cells of the brain, and their effects on the regulation of neurovascular remodeling and white matter remodeling after stroke are discussed.

Ischemia/Reperfusion Damage in Diabetic Stroke

Stroke is a leading cause of death and long-term disability. Patients with diabetes mellitus suffer from an increased risk of cardiovascular and cerebrovascular diseases including ischemic stroke. Diabetic stroke patients sustain worse neurological deficits and battle high mortality rates. Diabetes triggers a detrimental pathophysiological cascade resulting in severe vascular dysfunction and I/R injury which result in poor outcome after stroke in this population. The various aspects of diabetic stroke induced vascular and reperfusion damage and the underlying mechanisms are discussed in this chapter.

Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 Diabetic Rats

Angiopoietin-1 (Ang1) mediates vascular maturation and immune response. Diabetes decreases Ang1 expression and disrupts Ang1/Tie2 signaling activity. Vasculotide is an Ang1 mimetic peptide, and has anti-inflammatory effects. In this study, we test the hypothesis that vasculotide treatment induces neuroprotection and decreases inflammation after stroke in type 1 diabetic (T1DM) rats. T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with: 1) phosphate buffered saline (PBS); 2) vasculotide (3µg/kg, i.p. injection) administered half an hour prior to MCAo and at 8 and 24 hours after MCAo. Rats were sacrificed at 48 h after MCAo. Neurological function, infarct volume, hemorrhage, blood brain barrier (BBB) permeability and neuroinflammation were measured. Vasculotide treatment of T1DM-MCAo rats significantly improves functional outcome, decreases infarct volume and BBB permeability, but does not decrease brain hemorrhagic transformation compared with PBS-treated T1DM-MCAo rats. In the ischemic brain, Vasculotide treatment significantly decreases apoptosis, number of cleaved-caspase-3 positive cells, the expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF-α). Western blot analysis shows that vasculotide significantly decreases expression of receptor for advanced glycation end products (RAGE), MCP-1 and TNF-α in the ischemic brain compared with T1DM-MCAo rats. Vasculotide treatment in cultured primary cortical neurons (PCN) significantly decreases TLR4 expression compared with control. Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.