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p38 MAPK and PI3K/AKT Signalling Cascades inParkinson's Disease.

Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P - Int J Mol Cell Med (2015)

Bottom Line: These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD.Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades.In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi, India.

ABSTRACT
Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

No MeSH data available.


Related in: MedlinePlus

p38 MAPK interactions involved in Parkinson’s disease neuropathology and associated neurodegeneration. Neurotoxins viz. rotenone, maneb, paraquat and MPTP evokes numerous detrimental phenotypes in degenerating neurons and p38 MAPK is responsible for microglia activation, induction of oxidative stress, apoptosis, neuroinflammation and neurodegeneration as triggered by these toxins
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Figure 1: p38 MAPK interactions involved in Parkinson’s disease neuropathology and associated neurodegeneration. Neurotoxins viz. rotenone, maneb, paraquat and MPTP evokes numerous detrimental phenotypes in degenerating neurons and p38 MAPK is responsible for microglia activation, induction of oxidative stress, apoptosis, neuroinflammation and neurodegeneration as triggered by these toxins

Mentions: Human brain and immune system are convolutedly involved in a crosstalk so as to maintain tissue homeostasis. A panel of evidences obtained from human and animal research have advocated the principle that neuroinflammation significantly contributes to the neuronal loss in PD. Available reports highlight the centrality of non-cell-autonomous pathological mechanisms in PD, which in most cases are regulated by the activation of glial and peripheral immune population. Neuroinflammation in PD is a chronic mechanism that can be connected with the alteration of glial cells, including astrocytes and microglia. Microglia activation in PD brains acutely involves a panel of microglial-derived neurotoxic factors such as reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), elevated pro-inflammatory cytokine levels, and upregulated inflammatory-associated factors such as cyclooxygenase-2, which altogether cooperate to stabilize microglial response in PD brains (Figure 1). Therefore, and it is not surprising that the prolonged use of anti-inflammatory drugs can indeed reduce the risk for the disease. The neuronal response to microglia activation triggers unwanted trauma viz. oxidative stress (OS), neuroinflammation, cytokine-receptor-mediated apoptosis, which eventually contribute to DA neuronal mortality and subsequent disease progression. Interestingly, recent reports on transgenic mice related model mice were supportive of the idea that neuroinflammation in PD can be ambiguous, that is protective in the initial stages of degeneration but becomes severely damaging as the disease progresses (7, 38-40).


p38 MAPK and PI3K/AKT Signalling Cascades inParkinson's Disease.

Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P - Int J Mol Cell Med (2015)

p38 MAPK interactions involved in Parkinson’s disease neuropathology and associated neurodegeneration. Neurotoxins viz. rotenone, maneb, paraquat and MPTP evokes numerous detrimental phenotypes in degenerating neurons and p38 MAPK is responsible for microglia activation, induction of oxidative stress, apoptosis, neuroinflammation and neurodegeneration as triggered by these toxins
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499569&req=5

Figure 1: p38 MAPK interactions involved in Parkinson’s disease neuropathology and associated neurodegeneration. Neurotoxins viz. rotenone, maneb, paraquat and MPTP evokes numerous detrimental phenotypes in degenerating neurons and p38 MAPK is responsible for microglia activation, induction of oxidative stress, apoptosis, neuroinflammation and neurodegeneration as triggered by these toxins
Mentions: Human brain and immune system are convolutedly involved in a crosstalk so as to maintain tissue homeostasis. A panel of evidences obtained from human and animal research have advocated the principle that neuroinflammation significantly contributes to the neuronal loss in PD. Available reports highlight the centrality of non-cell-autonomous pathological mechanisms in PD, which in most cases are regulated by the activation of glial and peripheral immune population. Neuroinflammation in PD is a chronic mechanism that can be connected with the alteration of glial cells, including astrocytes and microglia. Microglia activation in PD brains acutely involves a panel of microglial-derived neurotoxic factors such as reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), elevated pro-inflammatory cytokine levels, and upregulated inflammatory-associated factors such as cyclooxygenase-2, which altogether cooperate to stabilize microglial response in PD brains (Figure 1). Therefore, and it is not surprising that the prolonged use of anti-inflammatory drugs can indeed reduce the risk for the disease. The neuronal response to microglia activation triggers unwanted trauma viz. oxidative stress (OS), neuroinflammation, cytokine-receptor-mediated apoptosis, which eventually contribute to DA neuronal mortality and subsequent disease progression. Interestingly, recent reports on transgenic mice related model mice were supportive of the idea that neuroinflammation in PD can be ambiguous, that is protective in the initial stages of degeneration but becomes severely damaging as the disease progresses (7, 38-40).

Bottom Line: These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD.Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades.In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi, India.

ABSTRACT
Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

No MeSH data available.


Related in: MedlinePlus