Reduced Dpp expression accelerates inflammation-mediated neurodegeneration through activated glial cells during altered innate immune response in Drosophila.

The progression of neurodegenerative disease is very complex biological process and the molecular crosstalk of inflammatory cytokines during neurodegeneration is associated with multiple cascade signalling. Few evidences suggest that environmental toxin, Paraquat (PQ) administration activates the microglia and intensify the release of proinflamatory cytokines during progression of Parkinson''s disease (PD) but the proper aetiology remained unknown. However, the fundamental role of anti-inflammatory molecule Decapentaplegic (Dpp), homologue of the secreted mammalian Transforming growth factor-ß (TGF-ß) signalling molecule during neurodegeneration of invertebrate fly model is yet to establish. To elucidate the molecular processes during early stage of Parkinson's disease, we observed neuro-toxin plays a determining role in the increased vulnerability to a particular PQ exposure that is attended by decreased lifespan, severe locomotor deficits, and more loss of dopaminergic (DA) neuron in PQ-treated Dpp deficient fly than wild type (WT). Simultaneously, activated microglia induced the inflammatory response with the release of pro-inflammatory and anti-inflammatory cytokine in Drosophila during neurodegeneration. Moreover, neuro-toxin exposure altered the expression of innate immune genes in both WT and mutant fly compared to the respective PQ-treated flies. Interestingly, PQ exposure reduced the expression of innate immune genes in mutant fly compared to WT. It may indicate that PQ exposure had broken down the immune defence response in mutant fly than WT whereas, without PQ exposure the innate immune tolerance level was higher in fly with reduced Dpp expression than WT. Thus, we observed the conserve anti-inflammatory factor TGF-ß may exhibit a crucial defensive role during inflammation mediated neurodegeneration in invertebrate Drosophila melanogaster.

Alterations of thyroidal status in brain regions and hypothalamo-pituitary-blood-thyroid-axis associated with dopaminergic depletion in substantia nigra and ROS formation in different brain regions after MPTP treatment in adult male mice.

MPTP produces oxidative stress, damages niagrostriatal dopaminergic neurons and develops Parkinsonism in rodents. Due to paucity of information, the thyroidal status in brain regions and peripheral tissues during different post-treatment days in MPTP-induced mice had been executed in the present study. MPTP depleted tyrosine hydroxylase protein expressions that signify the dopaminergic neuronal damage in substantia nigra. MPTP elevated ROS formation differentially in brain regions (cerebral cortex, hippocampus, substantia nigra) with maximal elevation at hippocampus. The changes in thyroid hormone (T4 and T3) levels indicate that brain regions might combat the adverse situation by keeping the levels of thyroid hormones either unchanged or in the elevated conditions in the latter phases (day-3 and day-7), apart from the depletion of thyroid hormones in certain brain regions (T4 in SN and hippocampus, T3 in hippocampus) as the immediate (day-1) effects after MPTP treatment. MPTP caused alterations of cellular morphology, RNA:Protein ratio and TPO protein expression, concomitantly depleted TPO mRNA expression and elevated TSH levels in the thyroid gland. Although T4 levels changed differentially, T3 levels remained unaltered in thyroid gland throughout the post-treatment days. Results have been discussed mentioning the putative role of T4 and TSH in apoptosis and/or proliferation/differentiation of thyrocytes. In blood, T4 levels remained unchanged while the changes in T3 and TSH levels did not signify the clinical feature of hypo/hyperthyroidism of animals. In the pituitary, both T4 and T3 levels remained elevated where TSH differentially altered (elevated followed by depletion) during post-treatment days. Notably, T4, T3 and TSH levels did not alter in hypothalamus except initial (day-1) depletion of the T4 level. Therefore, the feedback control mechanism of hypothalamo-pituitary-blood-thyroid-axis failed to occur after MPTP treatment. Overall, MPTP altered thyroidal status in the brain and peripheral tissues while both events might occur in isolation as well.

TNFR2 mediated TNF-α signaling and NF-κB activation in hippocampus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.

1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) -induced neuroinflammation and its impact in hippocampus remain elusive till date. Our present study includes the time dependent changes of inflammatory molecules in mouse hippocampus during MPTP treatment. MPTP treatment increased level of TNF-α, enhanced expression of TNFR2 along with PI3 kinase (PI3K) induced phosphorylation of Akt resulting in persistent nuclear factor-κB (NF-κB) activation. The expressions gradually increased from Day1 post-MPTP treatment, maximally at Day3 post-treatment. MPTP induced translocation of p65 and p52, two subunits of NF-κB family, to nucleus where they had been found to dimerize. Therefore, MPTP induced TNF-α signaling through TNFR2 mediated pathway and recruited p65-p52 dimer in hippocampal nucleus which is reported to have protective effect on hippocampal neurons indicated by unchanged neuronal count in hippocampus in treated groups with respect to control. Our finding suggests that this unique NF-κB dimer plays some role in providing inherent protection to hippocampus during MPTP-treatment.

Gender features and estrous cycle variations of nocturnal behavior of mice after a single exposure to light at night.

Light at night alters behavior and cognitive performances in rodents, the variations of which in gender and stages of reproductive cycle in females are elusive. Young mice habituated in light:dark (12:12h) cycle were given a single exposure of light (100lx) at early night for one hour duration followed by experimentations in open field (closed wall with circular big arena), elevated plus maze and square habituated field for memory performance using novel object recognition task. Light effects were compared with results found during without light conditions. Proestrous females appeared to have greater locomotor activity, less anxiety and better memory performance compared to the diestrous females at night without light exposure. The status of locomotor activity, anxiety and memory performance of male mice at night without light exposure appeared to be comparable to females where the stage of estrous cycle is important to characterize the nocturnal behavior of male mice. Light maximally affected proestrous females with decrease in locomotor activity, increase in anxiety and failure of memory performance. Male and diestrous female mice performed memory performance without alteration of locomotor activity and anxiety after exposure to light where males performed better memory performance with greater locomotor activity and more anxiety compared to that of diestrous females. The present study characterizes the mice nocturnal behavior with and without a single exposure to light stimuli with its gender features and estrous cycle variation. In addition, the study indicates an association of memory performance with locomotor activity and anxiety in mice nocturnal behavior.

Alteration of nuclear factor-kappaB pathway promote neuroinflammation depending on the functions of estrogen receptors in substantia nigra after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment.

The simultaneous role of neuroprotective estrogen and neurodegenerative inflammation during the progression of Parkinson's disease (PD) is still remaining elusive. The novel importance of the present study in MPTP mediated mouse model of Parkinson's disease (PD) is-to investigate the status of neuronal and glial cells in a time chase experiment; to explore which pathway of NF-kappaB exist to proceed the neuroinflammation; to investigate the status of estrogen and the activation pattern of nuclear or cytosolic estrogen receptors in either sexes of Swiss albino mice during MPTP mediated progressive neurodegeneration in the substantia nigra. After MPTP intoxication, the nigral molecular anatomy was changed differently in separate time interval during the progression of neurodegeneration with/without association of glial cells and functional (via its nuclear and cytosolic receptors) estrogen level. Both the canonical and/or non-canonical pathways of NF-kappaB exist in the substantia nigra of both the sexes after MPTP treatment that is why inspite of presence of estrogen, neuroinflammation progresses. The homodimeric or heterodimeric form of ER-beta binds with NF-kappaB molecules p65 and RelB differently, but the canonical or non-canonical pathways of NF-kappaB molecules could not be stopped or may be promoted.

Alteration in Nuclear Factor-KappaB Pathway and Functionality of Estrogen via Receptors Promote Neuroinflammation in Frontal Cortex after 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Treatment.

The MPTP mediated neurodegeneration in substantia nigra has been well studied, but not the status of frontal cortex. The novelty of the present study is to explore the sex difference of frontal cortex during MPTP intoxication and to investigate the role of estrogen and its receptors in presence of glial cells in a time chase experiment; to identify which pathway of NF-kappaB exist to proceed the neuroinflammation; to investigate the estrogen binding with its nuclear or cytosolic receptors and whether any direct relation exists between estrogen receptor (ER) -beta and NF-kappaB molecules p65 and RelB. The progression of neurodegeneration occurred with the association of glial cells and functional (via its nuclear and cytosolic receptors) estrogen level. Both the canonical and/or non canonical pathways of NF-kappaB exist in frontal cortex of both the sexes after MPTP treatment. The homodimeric or heterodimeric form of ER-beta binds with NF-kappaB molecules p65 and RelB differently, but the canonical or non canonical pathways of NF-kappaB molecules could not be stopped or may be promoted. The changes in the molecular and cellular pattern in frontal cortex of both sexes during MPTP intoxication depends on the estrogen function via its nuclear or cytosolic estrogen receptors.