Evaluation of GABA-chitosan nanoparticle induced cell signaling activation during liver regeneration after partial hepatectomy.

Liver damage due to infection, cirrhosis, accidents and diseases lead to destruction of hepatocytes and their regeneration to its original form is important for the proper functioning of the body. Gamma aminobutyric acid (GABA), a neurotransmitter, was coupled with a biopolymer chitosan and the nanosized complexes were made. The morphology was studied by scanning electron microscope and the interaction of GABA with chitosan was analysed by FT-IR spectroscopy. The interaction of GABA-chitosan nanoparticles with hepatocytes were observed by FITC labeled nanoparticles. After partial hepatectomy in male Wistar rats, DNA synthesis was estimated by tritiated thymidine uptake and the activity of thymidine kinase and protein synthesis by tritiated leucine uptake in hepatocytes. There was an increase in tritiated thymidine uptake in partially hepatectomised groups with nanoparticle treatment (GCNP) when compared to partially hepatectomised groups without nanoparticle treatment (PHNT) and with pure GABA treatment (G). Inositol 1,4,5 trisphosphate (IP3) content and gene expression of phospholipase C mRNA and nuclear factor kappa-light-chain-enhancer of activated B (NF-KB) mRNA was decreased for groups G and GCNP with respect to PHNT. Thus our results showed increased hepatocyte regeneration with decreased cell death in group G and more better with GCNP when compared to PHNT.

Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of unilateral 6-hydroxydopamine induced Parkinson's rats: effect of 5-HT, GABA and bone marrow cell supplementation.

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.

Glutamate and NMDA receptors activation leads to cerebellar dysfunction and impaired motor coordination in unilateral 6-hydroxydopamine lesioned Parkinson's rat: functional recovery with bone marrow cells, serotonin and GABA.

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.

Endocrine regulation of neonatal hypoxia: role of glucose, oxygen, and epinephrine supplementation.

Responses of the endocrine system are vital in revealing the mechanisms of respiratory activities. The present study focused on changes in insulin and triiodothyronine concentration in serum, its receptors in the hearts of hypoxic neonatal rats and glucose, oxygen, and epinephrine resuscitated groups. The insulin concentration was significantly increased with a significant upregulation of receptors in hypoxic neonates. Triiodothyronine content and its receptors were significantly decreased in serum and the hearts of hypoxic neonates. The change in hormonal levels is an adaptive modification of the endocrine system to encounter the stress. The effectiveness of glucose resuscitation to hypoxic neonates was also reported.

Opioid system functional regulation in neurological disease management.

There is increasing evidence to suggest a role for the opioid system in the control of pathophysiology of neurological disorders (Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, epilepsy, hypoxia, and autism). Resuscitation of the altered expression of the opioid system in various neurological disorders is of therapeutic importance. Such treatment may be beneficial in ameliorating the clinical symptoms of the disorder. This Mini-Review provides a brief update on opioid system regulation in neurological disorders and focuses on the opioids' pharmacological importance.

Dopamine D1 and D2 receptor functional down regulation in the cerebellum of hypoxic neonatal rats: neuroprotective role of glucose and oxygen, epinephrine resuscitation.

Brain damage due to an episode of hypoxia remains a major problem in infants causing deficit in motor and sensory function. Molecular processes regulating the dopamine receptors play a very important role in motor and cognitive functions. Disturbances in the development of the dopaminergic system lead to dyskinesia, dystonia, tics and abnormal eye movements. The present study is to understand the hypoxic damage to the dopamine content and dopamine D(1), dopamine D(2) receptors in cerebellum and the neuroprotective effect of glucose supplementation prior to the current sequence of resuscitation-oxygen and epinephrine supplementation in neonatal rats. Dopamine content in the cerebellum showed a significant decrease in hypoxic neonatal rats when compared to control. Dopamine D(1) and dopamine D(2) receptors showed a decrease in B(max) during hypoxia. The cerebellar dopamine, dopamine D(1) and dopamine D(2) receptors showed significant decrease on supplementation of 100% oxygen alone to hypoxic rats when compared to control rats. Dopamine D(1) and dopamine D(2) receptors mRNA showed significant decrease during epinephrine supplementation prior to resuscitation. These dopaminergic receptor alterations were reversed to near control by glucose supplementation. Thus our results suggest that glucose acts as a neuroprotective agent in dopaminergic receptors function. This has immense clinical significance to correct the resuscitation sequence in neonatal care.

Upregulation of 5-HT2C receptors in hippocampus of pilocarpine-induced epileptic rats: antagonism by Bacopa monnieri.

Emotional disturbances, depressive mood, anxiety, aggressive behavior, and memory impairment are the common psychiatric features associated with temporal lobe epilepsy (TLE). The present study was carried out to investigate the role of Bacopa monnieri extract in hippocampus of pilocarpine-induced temporal lobe epileptic rats through the 5-HT(2C) receptor in relation to depression. Our results showed upregulation of 5-HT(2C) receptors with a decreased affinity in hippocampus of pilocarpine-induced epileptic rats. Also, there was an increase in 5-HT(2C) gene expression and inositol triphosphate content in epileptic hippocampus. Carbamazepine and B. monnieri treatments reversed the alterations in 5-HT(2C) receptor binding, gene expression, and inositol triphosphate content in treated epileptic rats as compared to untreated epileptic rats. The forced swim test confirmed the depressive behavior pattern during epilepsy that was nearly completely reversed by B. monnieri treatment.

Tumor-derived fibulin-3 activates pro-invasive NF-κB signaling in glioblastoma cells and their microenvironment.

Molecular profiling of glioblastomas has revealed the presence of key signaling hubs that contribute to tumor progression and acquisition of resistance. One of these main signaling mechanisms is the nuclear factor-kappa B (NF-κB) pathway, which integrates multiple extracellular signals into transcriptional programs for tumor growth, invasion and maintenance of the tumor-initiating population. We show here that an extracellular protein released by glioblastoma cells, fibulin-3, drives oncogenic NF-κB in the tumor and increases NF-κB activation in peritumoral astrocytes. Fibulin-3 expression correlates with a NF-κB-regulated 'invasive signature' linked to poorer survival, being a possible tissue marker for regions of active tumor progression. Accordingly, fibulin-3 promotes glioblastoma invasion in a manner that requires NF-κB activation both in the tumor cells and their microenvironment. Mechanistically, we found that fibulin-3 activates the metalloprotease ADAM17 by competing with its endogenous inhibitor, TIMP3. This results in sustained release of soluble tumor necrosis factor alpha (TNFα) by ADAM17, which in turn activates TNF receptors and canonical NF-κB signaling. Taken together, our results underscore fibulin-3 as a novel extracellular signal with strong activating effect on NF-κB in malignant gliomas. Because fibulin-3 is produced de novo in these tumors and is absent from the normal brain, we propose that targeting the fibulin-3/NF-κB axis may provide a novel avenue to disrupt oncogenic NF-κB signaling in combination therapies for malignant brain tumors.

Oxidative stress mediated neuronal damage in the corpus striatum of 6-hydroxydopamine lesioned Parkinson's rats: neuroprotection by serotonin, GABA and bone marrow cells supplementation.

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.

Targeting glutamate mediated excitotoxicity in Huntington's disease: neural progenitors and partial glutamate antagonist--memantine.

Huntington's disease (HD) is a fatal progressive neurodegenerative disorder with autosomal dominant inheritance. In humans mutated huntingtin (htt) induces a preferential loss of medium spiny neurons (MSN) of the striatum and causes motor, cognitive and emotional deficits. One of the proposed cellular mechanism underlying medium spiny neurons degeneration is excitotoxic pathways mediated by glutamate receptors. The hypothesis proposed is restoration of medium spiny neurons in Huntington's disease using neural progenitor cell implantation and attenuation of glutamate mediated excitotoxicity using a partial glutamate antagonist - Memantine. Memantine can block the NMDA receptors and will prevent excess calcium influx into the neurons decreases the vulnerability of medium spiny neurons to glutamate mediated excitotoxicity. Neural progenitor cell implantation can enhance endogenous neurogenesis process replacing the degenerated medium spiny neurons in the striatum. This has immense significance in the management of Huntington's disease.

Dopamine D1 receptor gene expression studies in unilateral 6-hydroxydopamine-lesioned Parkinson's rat: effect of 5-HT, GABA, and bone marrow cell supplementation.

Parkinson's disease is the second most common neurodegenerative disorder and remains incurable. Many potential compensatory mechanisms have now been proposed; these are both dopaminergic, focused on enhancing effects or exposure to existing dopamine, and non-dopaminergic, being focused on reducing activity of the indirect striatal output pathway. In the present study, the effects of serotonin, gamma-aminobutyric acid, and bone marrow cell supplementation intranigrally to the substantia nigra on unilateral 6-hydroxydopamine-infused rats were analyzed individually. Dopaminergic binding parameters were done by Scatchard analysis of dopamine D(1) receptor-binding assay using [(3)H]SCH 23390. In the corpus striatum, 6-hydroxydopamine-infused rats showed a significant decrease in B (max) (P < 0.001), and in cerebral cortex, they showed a significant increase in B (max) (P < 0.001) compared to control. Real-time polymerase chain reaction amplification of dopamine D(1) was downregulated (P < 0.001) in the corpus striatum of 6-hydroxydopamine-infused rats compared to control, whereas in the cerebral cortex, it showed a significant upregulation (P < 0.001). Behavioral studies were carried out to confirm the biochemical and molecular studies. Serotonin and gamma-aminobutyric acid supplementation reversed these changes to control. The bone marrow cell-treated group of our studies does not show much significant change as compared to the serotonin and gamma-aminobutyric acid-supplemented groups. The alterations in dopamine D(1) receptor-binding parameters and gene expression during Parkinson's model were reversed by serotonin and gamma-aminobutyric acid supplementation in our experiments, which has clinical significance in the management of the disease.

Bacopa monnieri and Bacoside-A for ameliorating epilepsy associated behavioral deficits.

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.

Dopamine D1 and D2 receptor subtypes functional regulation in corpus striatum of unilateral rotenone lesioned Parkinson's rat model: effect of serotonin, dopamine and norepinephrine.

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.

Increased excitability and metabolism in pilocarpine induced epileptic rats: effect of Bacopa monnieri.

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.