Tahira Farooqui

Modulation of inflammation in brain: a matter of fat

Neuroinflammation is a host defense mechanism associated with neutralization of an insult and restoration of normal structure and function of brain. Neuroinflammation is a hallmark of all major CNS diseases. The main mediators of neuroinflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidation of AA produces pro‐inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso‐glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro‐inflammatory platelet‐activating factor. These pro‐inflammatory mediators intensify neuroinflammation. Lipoxin, an oxidized product of AA through 5‐lipoxygenase, is involved in the resolution of inflammation and is anti‐inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuroinflammation by inhibiting transcription factor NFκB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter‐balancing the harmful effects of high levels of AA‐derived pro‐inflammatory lipid mediators.

Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders.

Neural membranes contain several classes of glycerophospholipids which turnover at different rates with respect to their structure and localization in different cells and membranes. The glycerophospholipid composition of neural membranes greatly alters their functional efficacy. The length of glycerophospholipid acyl chain and the degree of saturation are important determinants of many membrane characteristics including the formation of lateral domains that are rich in polyunsaturated fatty acids. Receptor-mediated degradation of glycerophospholipids by phospholipases A(l), A(2), C, and D results in generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor and diacylglycerol. Thus, neural membrane phospholipids are a reservoir for second messengers. They are also involved in apoptosis, modulation of activities of transporters, and membrane-bound enzymes. Marked alterations in neural membrane glycerophospholipid composition have been reported to occur in neurological disorders. These alterations result in changes in membrane fluidity and permeability. These processes along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for the neurodegeneration observed in neurological disorders.

Modulation of Early Olfactory Processing by an Octopaminergic Reinforcement Pathway in the Honeybee

Processing of olfactory information in the antennal lobes of insects and olfactory bulbs of vertebrates is modulated by centrifugal inputs that represent reinforcing events. Octopamine release by one such pathway in the honeybee antennal lobe modulates olfactory processing in relation to nectar (sucrose) reinforcement. To test more specifically what role octopamine plays in the antennal lobe, we used two treatments to disrupt an octopamine receptor from Apis mellifera brain (AmOAR) function: (1) an OAR antagonist, mianserin, was used to block receptor function, and (2) AmOAR double-stranded RNA was used to silence receptor expression. Both treatments inhibited olfactory acquisition and recall, but they did not disrupt odor discrimination. These results suggest that octopamine mediates consolidation of a component of olfactory memory at this early processing stage in the antennal lobe. Furthermore, after consolidation, octopamine release becomes essential for recall, which suggests that the modulatory circuits become incorporated as essential components of neural representations that activate odor memory.

Aging: an important factor for the pathogenesis of neurodegenerative diseases.

Aging is a natural process that is defined as a progressive deterioration of biological functions after the organism has attained its maximal reproductive competence. Aging leads to the accumulation of disabilities and diseases that limit normal body functions and is a major risk factor for neurodegenerative diseases. Many neurodegenerative diseases share oxidative stress and nitrosative stress as common terminal processes. According to free radical theory of aging, an elevation in reactive oxygen species (ROS) and reactive nitrogen species (RNS) damages neural membranes and induces oxidative and nitrosative stress. The increase in oxidative and nitrosative stress is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Markedly increased rates of oxidative and nitrosative stress are the major factors associated with the pathogenesis of neurodegenerative diseases. Diet is a key environmental factor that affects the incidence of chronic neurodegenerative diseases. Dietary supplementation with polyphenols, resveratrol, ginkgo biloba, curcumin, ferulic acid, carotenoids, flavonoids, and n-3 fatty acids exerts beneficial effects not only through the scavenging of free radicals, but also by modulating signal transduction, gene expression, and restoring optimal neuronal communication.

Octopamine-Mediated Neuromodulation of Insect Senses

Octopamine functions as a neuromodulator, neurotransmitter, and neurohormone in insect nervous systems. Octopamine has a prominent role in influencing multiple physiological events: (a) as a neuromodulator, it regulates desensitization of sensory inputs, arousal, initiation, and maintenance of various rhythmic behaviors and complex behaviors such as learning and memory; (b) as a neurotransmitter, it regulates endocrine gland activity; and (c) as a neurohormone, it induces mobilization of lipids and carbohydrates. Octopamine exerts its effects by binding to specific proteins that belong to the superfamily of G protein-coupled receptors and share the structural motif of seven transmembrane domains. The activation of octopamine receptors is coupled with different second messenger pathways depending on species, tissue source, receptor type and cell line used for the expression of cloned receptor. The second messengers include adenosine 3′,5′-cyclic monophosphate (cAMP), calcium, diacylglycerol (DAG), and inositol 1,4,5-trisphosphate (IP3). The cAMP activates protein kinase A, calcium and DAG activate protein kinase C, and IP3 mobilizes calcium from intracellular stores. Octopamine-mediated generation of these second messengers is associated with changes in cellular response affecting insect behaviors. The main objective of this review is to discuss significance of octopamine-mediated neuromodulation in insect sensory systems.

Inhibitors of intracellular phospholipase A2 activity: their neurochemical effects and therapeutical importance for neurological disorders.

Intracellular phospholipases A2 (PLA2) are a diverse group of enzymes with a growing number of members. These enzymes hydrolyze membrane phospholipids into fatty acid and lysophospholipids. These lipid products may serve as intracellular second messengers or can be further metabolized to potent inflammatory mediators, such as eicosanoids and platelet-activating factors. Several inhibitors of nonneural intracellular PLA2 have been recently discovered. However, nothing is known about their neurochemical effects, mechanism of action or toxicity in human or animal models of neurological disorders. Elevated intracellular PLA2 activities, found in neurological disorders strongly associated with inflammation and oxidative stress (ischemia, spinal cord injury, and Alzheimers disease), can be treated with specific, potent and nontoxic inhibitors of PLA2 that can cross blood-brain barrier without harm. Currently, potent intracellular PLA2 inhibitors are not available for clinical use in human or animal models of neurological disorders, but studies on this interesting topic are beginning to emerge. The use of nonspecific intracellular PLA2 inhibitors (quinacrine, heparin, gangliosides, vitamin E) in animal model studies of neurological disorders in vivo has provided some useful information on tolerance, toxicity, and effectiveness of these compounds.

Deacylation and reacylation of neural membrane glycerophospholipids.

The deacylation-reacylation cycle is an important mechanism responsible for the introduction of polyunsaturated fatty acids into neural membrane glycerophospholipids. It involves four enzymes, namely acyl-CoA synthetase, acyl-CoA hydrolase, acyl-CoA: lysophospholipid acyltransferase, and phospholipase A2. All of these enzymes have been purified and characterized from brain tissue. Under normal conditions, the stimulation of neural membrane receptors by neurotransmitters and growth factors results in the release of arachidonic acid from neural membrane glycerophospholipids. The released arachidonic acid acts as a second messenger itself. It can be further metabolized to eicosanoids, a group of second messengers involved in a variety of neurochemical functions. A lysophospholipid, the second product of reactions catalyzed by phospholipase A2, is rapidly acylated with acyl-CoA, resulting in the maintenance of the normal and essential neural membrane glycerophospholipid composition. However, under pathological situations (ischemia), the overstimulation of phospholipase A2 results in a rapid generation and accumulation of free fatty acids including arachidonic acid, eicosanoids, and lipid peroxides. This results in neural inflammation, oxidative stress, and neurodegeneration. In neural membranes, the deacylation-reacylation cycle maintains a balance between free and esterified fatty acids, resulting in low levels of arachidonic acid and lysophospholipids. This is necessary for not only normal membrane integrity and function, but also for the optimal activity of the membrane-bound enzymes, receptors, and ion channels involved in normal signal-transduction processes.

Metabolic syndrome as a risk factor for neurological disorders

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.

Lipid-Mediated Oxidative Stress and Inflammation in the Pathogenesis of Parkinson's Disease

Parkinsons disease (PD) is a neurodegenerative movement disorder of unknown etiology. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, depletion of dopamine in the striatum, abnormal mitochondrial and proteasomal functions, and accumulation of α-synuclein that may be closely associated with pathological and clinical abnormalities. Increasing evidence indicates that both oxidative stress and inflammation may play a fundamental role in the pathogenesis of PD. Oxidative stress is characterized by increase in reactive oxygen species (ROS) and depletion of glutathione. Lipid mediators for oxidative stress include 4-hydroxynonenal, isoprostanes, isofurans, isoketals, neuroprostanes, and neurofurans. Neuroinflammation is characterized by activated microglial cells that generate proinflammatory cytokines, such as TNF-α and IL-1β. Proinflammatory lipid mediators include prostaglandins and platelet activating factor, together with cytokines may play a prominent role in mediating the progressive neurodegeneration in PD.

Interactions between neural membrane glycerophospholipid and sphingolipid mediators: A recipe for neural cell survival or suicide

The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A2 (PLA2) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1‐phosphate, sphingosine, and sphingosine 1‐phosphate. These metabolites modulate PLA2 activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA2, modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1‐phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA2 and SMase inhibitors can be used as neuroprotective and anti‐apoptotic agents. Development of novel inhibitors of PLA2 and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.