ABSTRACT
Pulmonary hypertension (PH) is a complex and multifactorial disease. An inability to fully unravel the molecular complexities has led to various clinical challenges in developing new therapies for this disease. Noncoding RNAs (ncRNAs) are RNA molecules with limited ability of coding proteins. The amount of ncRNAs is up to 98% of the whole genome's transcripts. Many ncRNAs with a regulatory function of genes have been identified to date and found to act at various steps along the protein biosynthetic process, which includes transcription, RNA maturation, translation, and protein degradation. These discoveries are fueling a new era in understanding the pathophysiology and therapeutic pathways of PH. In this chapter, we discuss the emerging role of noncoding RNAs in PH as well as other pulmonary diseases.
Subject(s)
Lung Diseases/genetics , Lung Neoplasms/genetics , Lung/metabolism , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Animals , Gene Expression Regulation , Genetic Predisposition to Disease/genetics , Humans , Hypertension, Pulmonary/genetics , Pulmonary Disease, Chronic Obstructive/geneticsABSTRACT
Oxidative stress-induced neuronal cell death has been implicated in Parkinson's disease (PD). Oxidative stress initiated by 6-hydroxydopamine (6-OHDA) causes mitochondrial dysfunction leading to apoptosis and Parkinsonian neurodegeneration. We investigated the neuroprotective potential of serotonin (5-HT), gamma amino butyric acid (GABA) and autologous bone marrow cells (BMC) in combination against oxidative stress-induced cell death. PD was induced in adult male Wistar rats by intranigral infusion of 6-OHDA (8 µg/µl). The activities of antioxidant enzymes--superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were analysed. The extent of lipid peroxidation was quantified by measuring the formation of thiobarbituric acid reactive substances (TBARs). Real Time PCR gene expression of SOD, CAT and GPx were performed using specific Taqman probes. 6-OHDA induced decreased activity of SOD, CAT and GPx in corpus striatum was significantly reversed to near control (p<0.001) by treatment with 5-HT, GABA and bone marrow cells. Gene expression studies of SOD, CAT and GPx using Real Time PCR confirmed the above observation. TBAR levels were elevated (p<0.001) in 6-OHDA treated rats indicating lipid peroxidation. 5-HT and GABA along with autologous bone marrow cell supplementation significantly ameliorated 6-OHDA-induced lipid peroxidation (p<0.001). Our results suggest a new therapeutic strategy of neuroprotection against damage by oxidative stress in Parkinson's disease.
Subject(s)
Adrenergic Agents/toxicity , Bone Marrow Transplantation/methods , Corpus Striatum , Oxidopamine/toxicity , Parkinson Disease , Serotonin/therapeutic use , gamma-Aminobutyric Acid/therapeutic use , Analysis of Variance , Animals , Catalase/genetics , Catalase/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/pathology , Disease Models, Animal , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Lipid Peroxidation/drug effects , Male , Oxidative Stress/drug effects , Oxidative Stress/physiology , Parkinson Disease/etiology , Parkinson Disease/pathology , Parkinson Disease/therapy , Rats , Rats, Wistar , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
Complications arising from diabetes mellitus include cognitive deficits, neurophysiological and structural changes in the brain. The current study investigated the expression of cholinergic, insulin, Vitamin D receptor and GLUT 3 in the brainstem of streptozotocin-induced diabetic rats. Radioreceptor binding assays and gene expression were done in the brainstem of male Wistar rats. Our results showed that B(max) of total muscarinic, muscarinic M3 receptors was increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. A significant increase in gene expression of muscarinic M3, α7 nicotinic acetylcholine, insulin, Vitamin D3 receptors, acetylcholine esterase, choline acetyl transferase and GLUT 3 were observed in the brainstem of diabetic rats. Immunohistochemistry studies of muscarinic M1, M3 and α7 nicotinic acetylcholine receptors confirmed the gene expression at protein level. Vitamin D3 and insulin treatment reversed diabetes-induced alterations to near control. This study provides an evidence that diabetes can alter the expression of cholinergic, insulin, Vitamin D receptors and GLUT 3 in brainstem. We found that Vitamin D3 treatment could modulate the Vitamin D receptors and plays a pivotal role in maintaining the glucose transport and expressional level of cholinergic receptors in the brainstem of diabetic rats. Thus, our results suggest a therapeutic role of Vitamin D3 in managing neurological disorders associated with diabetes.
Subject(s)
Brain Stem/metabolism , Cholecalciferol/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/physiopathology , Glucose Transporter Type 3/biosynthesis , Receptor, Insulin/biosynthesis , Receptors, Calcitriol/biosynthesis , Receptors, Nicotinic/biosynthesis , Animals , Blood Glucose/metabolism , Insulin/blood , Insulin/therapeutic use , Male , Rats , Rats, Wistar , Receptor, Muscarinic M1/biosynthesis , Receptor, Muscarinic M3/metabolism , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterised by a profound and selective loss of nigrostriatal dopaminergic neurons. In Parkinson's disease, degeneration of dopaminergic neurons involves motor structures including basal ganglia and cerebellum. Glutamate-mediated degeneration of the cerebellum contributes to motor dysfunction in Parkinson's disease. Targeting neurotransmitter system beyond the dopamine system is of important, both for the motor and for the nonmotor problems of Parkinson's disease. The aim of this study is to assess the glutamate and NMDA receptor functional regulation and motor performance of 6-hydroxydopamine-induced Parkinson's rat and the effects of serotonin (5-HT), gamma aminobutyric acid (GABA) and bone marrow cells supplementation infused intranigrally to substantia nigra individually and in combination. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in B (max) (P < 0.001) in the cerebellum of 6-hydroxydopamine infused rat compared to control. Real-Time PCR amplification of NMDA2B, mGluR5, and bax were significantly (P < 0.001) upregulated in cerebellum of 6-hydroxydopamine infused rats compared to control. Activation of the glutamate and NMDA receptors gave rise to an increased cAMP and IP3 content in the cerebellum. Gene expression studies of GLAST and CREB showed a significant (P < 0.001) down regulation in 6-OHDA infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies. Serotonin and GABA along with bone marrow cells in combination showed reversal of glutamate receptors and motor abnormality shown in the Parkinson's rat model. The therapeutic significance in Parkinson's disease is of prominence.
Subject(s)
Cerebellar Diseases/physiopathology , Motor Activity/physiology , Parkinson Disease, Secondary/physiopathology , Receptors, Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Binding, Competitive , Cerebellar Diseases/chemically induced , Cerebellar Diseases/therapy , Cerebellum/metabolism , Cerebellum/physiopathology , Cyclic AMP/metabolism , Dizocilpine Maleate/metabolism , Inositol Phosphates/metabolism , Male , Microscopy, Confocal , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/therapy , Rats , Rats, Wistar , Receptor, Metabotropic Glutamate 5 , Receptors, Glutamate/genetics , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Reverse Transcriptase Polymerase Chain Reaction , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
Parkinson's disease is a progressive neurodegenerative disorder characterized by selective degeneration of dopaminergic neurons in substantia nigra pars compacta leading to marked reduction of dopamine levels in the cerebral cortex. The present study analysed the effect of serotonin, dopamine and norepinephrine as treatment on rotenone induced Hemi-Parkinson's disease in rats and its role in the regulation of dopamine receptor subtypes in the cerebral cortex of the experimental rats. Unilateral stereotaxic single dose infusions of rotenone were administered to the substantia nigra of adult male Wistar rats. Neurotransmitters--serotonin, dopamine and norepinephrine treatments--were given to rotenone induced Hemi-Parkinson's rats. Scatchard analysis of Dopamine D1 and D2 receptor showed a significant increase (p < 0.001) in the cerebral cortex of the Parkinson's rats compared to control. These altered parameters were reversed to near control in the serotonin and norepinephrine treated Parkinson's disease rats and no change was observed in dopamine treated Parkinson's rats. Real-time PCR results confirmed the receptor data. Our results showed serotonin and norepinephrine functionally reversed the dopamine receptors significantly in rotenone induced Hemi-Parkinson's rat. This has clinical significance in the therapeutic management of Parkinson's disease.
Subject(s)
Cerebral Cortex/drug effects , Neurotransmitter Agents/pharmacology , Parkinsonian Disorders/drug therapy , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Animals , Dopamine/metabolism , Dopamine/pharmacology , Functional Laterality , Male , Norepinephrine/metabolism , Norepinephrine/pharmacology , Parkinsonian Disorders/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Rotenone/toxicity , Serotonin/metabolism , Serotonin/pharmacology , Uncoupling Agents/toxicityABSTRACT
Parkinson's disease is characterized by progressive cell death in the substantia nigra pars compacta, which leads to dopamine depletion in the striatum and indirectly to cortical dysfunction. Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease and glutamate receptor mediated excitotoxicity has been suggested to be one of the possible causes of the neuronal degeneration. In the present study, the effects of serotonin, gamma-aminobutyric acid and bone marrow cells infused intranigrally to substantia nigra individually and in combination on unilateral 6-hydroxydopamine induced Parkinson's rat model was analyzed. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in Bmax (P < 0.001) in the cerebral cortex of 6-hydroxydopamine infused rat compared to control. Real Time PCR amplification of NMDA2B, mGluR5, bax, and ubiquitin carboxy-terminal hydrolase were up regulated in cerebral cortex of 6-hydroxydopamine infused rats compared to control. Gene expression studies of GLAST, ά-Synuclien and Cyclic AMP response element-binding protein showed a significant (P < 0.001) down regulation in 6-OHDA infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies. Serotonin and GABA along with bone marrow cells in combination showed reversal of glutamate receptors and behaviour abnormality shown in the Parkinson's rat model. The therapeutic significance in Parkinson's disease is of prominence.
Subject(s)
Bone Marrow Transplantation , Cerebral Cortex/metabolism , Cyclic AMP/metabolism , Glutamic Acid/metabolism , Inositol Phosphates/metabolism , Oxidopamine/adverse effects , Parkinson Disease, Secondary/metabolism , Serotonin/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Behavior, Animal/drug effects , Bone Marrow Cells/metabolism , Cerebral Cortex/pathology , Disease Models, Animal , Male , Oxidopamine/pharmacology , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/pathology , Parkinson Disease, Secondary/therapy , Rats , Rats, Wistar , Substantia Nigra/metabolism , Substantia Nigra/pathology , Transplantation, HomologousABSTRACT
UNLABELLED: Parkinson's disease (PD) is due to widespread degeneration in the central and peripheral nervous systems. The hallmark pathology remains in the dopaminergic striatal insufficiency and degeneration of dopaminergic neurons in the substantia nigra. OBJECTIVES: The present study analysed the effect of serotonin (5-HT), dopamine, and norepinephrine as treatment on rotenone induced hemi-Parkinson's disease in rats and its role in the regulation of dopamine receptor subtypes in the corpus striatum of the experimental rats. METHODS: Unilateral stereotaxic single-dose infusions of rotenone were administered to the substantia nigra of adult male Wistar rats. Neurotransmitters serotonin (5-HT), dopamine, and norepinephrine treatments were given to rotenone induced hemi-Parkinson's rats. Dopamine receptor and its subtypes (D1 and D2) binding assay were carried out. Gene expression studies of dopamine D1 and D2 were carried out using real-time PCR. RESULTS: Scatchard analysis of dopamine and dopamine D2 receptor showed a significant increase (P<0.001) and dopamine D1 receptor showed a significant decrease (P<0.001) in the B(max) in corpus striatum of the PD rats compared to control. These altered parameters were reversed to near control in the serotonin- and norepinephrine-treated PD rats and no change was observed in dopamine-treated PD rats. Real-time PCR results confirmed the receptor data. CONCLUSION: Our results showed that serotonin and norepinephrine functionally reversed in dopamine receptors in rotenone-induced hemi-Parkinson's rat. This has clinical significance in the therapeutic management of PD.
Subject(s)
Catecholamines/pharmacology , Corpus Striatum/drug effects , Parkinsonian Disorders/pathology , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Animals , Benzamides/pharmacokinetics , Benzazepines/pharmacokinetics , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/pharmacology , Dopamine Antagonists/pharmacokinetics , Dopamine D2 Receptor Antagonists , Drug Interactions , Functional Laterality , Male , Norepinephrine/pharmacology , Parkinsonian Disorders/chemically induced , Protein Binding/drug effects , Radionuclide Imaging , Rats , Rats, Wistar , Rotarod Performance Test , Rotenone/analogs & derivatives , Serotonin/pharmacology , Tritium/pharmacokineticsABSTRACT
OBJECTIVE: In this work, we evaluated the differential binding of serotonin 2A (5-HT(2A)) receptor antagonist [(3)H](+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] ([(3)H] MDL 100907) to 5-HT(2A) receptors in cerebral cortex and liver. METHODS: Wistar adult male rats of 180-200 g body weight were given free access to 15% (v/v; approximately 7.5 g/kg body weight per day) ethanol for 15 days. Brain 5-HT and its metabolites were assayed by a high-performance liquid chromatography. 5-HT(2A) receptor binding assay was done with different concentrations of [(3)H] MDL 100907. Hepatocyte culture was done with 10(-9)-10(-3)M of 5-HT and ketanserin. The hepatocytes were incubated for 24 hours at 37 degrees C in 5% CO(2). RESULTS: Decreased 5-HT content (p<0.05 and p<0.001) and decreased (p<0.001) 5-HT(2A) receptor binding in cerebral cortex and liver of ethanol-treated rats were observed when compared with control. 5-HT(2A) receptor mRNA in the cerebral cortex and liver showed an increase in crossing threshold value showing decrease in gene expression in ethanol-treated rats when compared with control. In 24-hour culture works, hepatocytes with 10% ethanol showed an increase in aldehyde dehydrogenase (ALDH) activity (p<0.001), and it decreased (p<0.001) to a near-control level in the case of hepatocytes in a medium with 10% ethanol + 10(-5)M 5-HT and 10% ethanol + 10(-7)M 5-HT when compared with the hepatocytes in the medium with 10% ethanol. CONCLUSION: Our results suggest that the decreased serotonin function mediated through 5-HT(2A) receptors have a regulatory role on ALDH activity. This will have clinical significance to correct alcoholics from addiction due to allergic aldehyde accumulation.
Subject(s)
Aldehyde Dehydrogenase/metabolism , Central Nervous System Depressants/pharmacology , Cerebral Cortex/drug effects , Ethanol/pharmacology , Liver/drug effects , Receptor, Serotonin, 5-HT2A/metabolism , Aging , Animals , Cells, Cultured , Cerebral Cortex/enzymology , Cerebral Cortex/metabolism , Gene Expression/drug effects , Hepatocytes/drug effects , Hepatocytes/enzymology , Hepatocytes/metabolism , Liver/enzymology , Liver/metabolism , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A/genetics , Serotonin/metabolismABSTRACT
We have evaluated the acetylcholine esterase and malate dehydrogenase activity in the muscle, epinephrine, norepinephrine, insulin and T3 content in the serum of epileptic rats. Acetylcholine esterase and malate dehydrogenase activity increased in the muscle and decreased in the heart of the epileptic rats compared to control. Insulin and T3 content were increased significantly in the serum of the epileptic rats. Our results suggest that repetitive seizures resulted in increased metabolism and excitability in epileptic rats. Bacopa monnieri and Bacoside-A treatment prevents the occurrence of seizures there by reducing the impairment on peripheral nervous system.
Subject(s)
Anticonvulsants/therapeutic use , Bacopa , Epilepsy/drug therapy , Phytotherapy , Saponins/therapeutic use , Triterpenes/therapeutic use , Acetylcholinesterase/metabolism , Animals , Carbamazepine/therapeutic use , Epilepsy/chemically induced , Epilepsy/metabolism , Epinephrine/blood , Insulin/blood , Malate Dehydrogenase/metabolism , Male , Muscarinic Agonists , Myocardium/enzymology , Norepinephrine/blood , Pilocarpine , Plant Extracts/therapeutic use , Rats , Rats, Wistar , Triiodothyronine/bloodABSTRACT
Oxidative stress plays an important role in cerebellar damage caused by diabetes, leading to deterioration in glucose homeostasis causing metabolic disorders. The present study was carried out to find the effects of Aegle marmelose leaf extract and insulin alone and in combination with pyridoxine on the cerebellar 5-HT through 5-HT(2A) receptor subtype, gene expression studies on the status of antioxidants-superoxide dismutase (SOD), glutathione peroxidase (GPx), 5-HT(2A) and 5-HT transporter (5-HTT) and immunohistochemical studies in streptozotocin induced diabetic rats. 5-HT and 5-HT(2A) receptor binding parameters, B(max) and K(d), showed a significant decrease (p<0.001) in the cerebellum of diabetic rats compared to control. Gene expression studies of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum showed a significant down regulation (p<0.001) in diabetic rats compared to control. Pyridoxine treated alone and in combination with insulin, A. marmelose to diabetic rats reversed the B(max), K(d) of 5-HT, 5-HT(2A) and the gene expression of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum to near control. The gene expression of 5-HT(2A) and 5-HTT were confirmed by immunohistochemical studies. Also, the Rotarod test confirms the motor dysfunction and recovery by treatment. These data suggest the antioxidant and neuroprotective role of pyridoxine and A. marmelose through the up regulation of 5-HT through 5-HT(2A) receptor in diabetic rats. Our results suggest that pyridoxine treated alone and in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalizing diabetic related oxidative stress and neurodegeneration affecting the motor ability of an individual by serotonergic receptors through 5-HT(2A) function. This has clinical significance in the management of diabetes.
Subject(s)
Aegle/chemistry , Cerebellum/drug effects , Diabetes Mellitus, Experimental/metabolism , Plant Extracts/pharmacology , Pyridoxine/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Animals , Blood Glucose/metabolism , Cerebellum/metabolism , Insulin/pharmacology , Male , Random Allocation , Rats , Rats, Wistar , Rotarod Performance Test , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Vitamin B Complex/pharmacologySubject(s)
Benzodiazepines/administration & dosage , Brain Diseases/drug therapy , Brain Diseases/metabolism , Cerebral Palsy/drug therapy , Cerebral Palsy/metabolism , Glutamic Acid/metabolism , Receptors, AMPA/antagonists & inhibitors , Brain Diseases/complications , Cerebral Palsy/etiology , Humans , Models, NeurologicalABSTRACT
Bacopa monnieri is an outstanding nervine tonic used for raising the mental performance. It helps in concentration, comprehension, recall and alertness, Brahmi is particularly beneficial as it aids in categorizing information in brain and its subsequent expression. Bacopa is also called as a natural antioxidant which may give details its neuroprotective role seen in the memory centers of the brain. Epilepsy is neuronal disorder characterized by learning, cognitive and memory impairments. The present review summarizes information concerning botany, chemistry and beneficial effect of Bacopa monnieri on epilepsy associated behavioral deficits.
Subject(s)
Antioxidants/therapeutic use , Bacopa/chemistry , Cognition/drug effects , Epilepsy/drug therapy , Phytotherapy , Plant Extracts/therapeutic use , Saponins/therapeutic use , Triterpenes/therapeutic use , Animals , Antioxidants/pharmacology , Epilepsy/psychology , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Plant Extracts/pharmacology , Saponins/pharmacology , Triterpenes/pharmacologyABSTRACT
Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through 5HT(2C) receptors. 5-HT(2C) receptors are novel targets for developing anti-convulsant drugs. In the present study, we investigated the changes in the 5-HT(2C) receptors binding and gene expression in the cerebellum of control, epileptic and Bacopa monnieri treated epileptic rats. There was a significant down regulation of the 5-HT content (p<0.001), 5-HT(2C) gene expression (p<0.001) and 5-HT(2C) receptor binding (p<0.001) with an increased affinity (p<0.001). Carbamazepine and B. monnieri treatments to epileptic rats reversed the down regulated 5-HT content (p<0.01), 5-HT(2C) receptor binding (p<0.001) and gene expression (p<0.01) to near control level. Also, the Rotarod test confirms the motor dysfunction and recovery by B. monnieri treatment. These data suggest the neuroprotective role of B. monnieri through the upregulation of 5-HT(2C) receptor in epileptic rats. This has clinical significance in the management of epilepsy.