The central nervous system is exposed to the chronic oxidative stress during aging when the endogenous defence weakens and the load of reactive oxygen species enhances. Sex hormones and heat shock proteins (Hsps) participate in these responses to stress. Their regulation is disturbed in aging. We assessed the expression of Hsps in hippocampus and cortex of follitropin receptor knockout (FORKO) mice, known to exhibit gender and age-dependent imbalance in sex steroids and gonadotropins. These imbalances could contribute to an impaired regulation of Hsps thereby increasing the risk of developing neurodegenerative disorders. Our study shows that, in the hippocampus the expression of Hsp70 and Hsp25 was reduced in 20-month-old FORKO mice. However, in the cortex both Hsps were significantly down regulated only in elderly females. There is a well-established co-regulation between Hsps and mitogen-activated protein kinases (MAPKs). Significant, gender-specific impairments in the translocation of phosphorylated ERK and JNK were found in the CNS structures in aged FORKO mice. Our results suggest that hormonal imbalances lead to a disturbed subcellular distribution of activated MAPKs which contribute to the impairments of signal transduction networks maintaining normal physiological functions in the cortex and hippocampus that are associated with neurodegenerative changes in aging.
"The brain is exposed to chronic oxidative stress during aging (Rastogi et al. 2012). As result, there is a gradual accumulation of damaged proteins and a functional decline in the brain's endogenous defense system (Rumora et al. 2007; Min et al. 2008). Our results clearly indicated that levels of HSP 70 were decreased in the dentate gyrus of old male rats. "
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that the age-related decrease in the number of neurons in the hippocampus that leads to alterations in brain function, may be associated with an increase in apoptosis due to the reduced secretion of growth hormone (GH) and/or melatonin in old animals. In order to investigate this possibility, male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (hGH) for 10 weeks (2 mg/kg/d sc) and the third was subjected to melatonin treatment (1 mg/kg/d) in the drinking water for the same time. A group of 2-months-old male rats was used as young controls. All rats were killed by decapitation at more than 24 month of age and dentate gyri of the hippocampi were collected. Aging in the dentate gyrus was associated with an increase in apoptosis promoting markers (Bax, Bad and AIF) and with the reduction of some anti-apoptotic ones (XIAP, NIAP, Mcl-1). Expressions of sirtuin 1 and 2 (SIRT1 and 2) as well as levels of HSP 70 were decreased in the dentate gyrus of old rats. GH treatment was able to reduce the pro/anti-apoptotic ratio to levels observed in young animals and also to increase SIRT2. Melatonin reduced also expression of pro-apoptotic genes and proteins (Bax, Bad and AIF), and increased levels of myeloid cell leukemia-1 proteins and SIRT1. Both treatments were able to reduce apoptosis and to enhance survival markers in this part of the hippocampus.
"The spatial-temporal regulation of JNK is differently regulated in multiple intracellular compartments (Bonny et al. 2005, Borsello & Forloni 2007). Many studies indicate that JNK could be activated in or translocate to mitochondria, including work in ischemia-injured hippocampus, mouse cardiac mitochondria, H 2 O 2 -treated rat brain or primary cortical cultures, acetaminophen induced liver injury, HeLa cells treated with paclitaxel, and multiple myeloma cells treated with anti-cancer drugs (Baines et al. 2002, Chauhan et al. 2003, Zablocka et al. 2003, Brichese et al. 2004, Rumora et al. 2007, Hanawa et al. 2008, Zhou et al. 2008b). While most studies including those discussed below implicate JNK in death signaling, JNK shows neuroprotective effects in hypoxiareoxygenation studies (Dougherty et al. 2004). "
[Show abstract][Hide abstract] ABSTRACT: Alterations in mitochondrial biology have long been implicated in neurotoxin, and more recently, genetic models of parkinsonian neurodegeneration. In particular, kinase regulation of mitochondrial dynamics and turnover are emerging as central mechanisms at the convergence of neurotoxin, environmental and genetic approaches to studying Parkinson's disease (PD). Kinases that localize to mitochondria during neuronal injury include mitogen activated protein kinases (MAPK) such as extracellular signal regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK), protein kinase B/Akt, and PTEN-induced kinase 1 (PINK1). Although site(s) of action within mitochondria and specific kinase targets are still unclear, these signaling pathways regulate mitochondrial respiration, transport, fission-fusion, calcium buffering, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death. In this review, we summarize accelerating experimental evidence gathered over the last decade that implicate a central role for kinase signaling at the mitochondrion in Parkinson's and related neurodegenerative disorders. Interactions involving alpha-synuclein, leucine rich repeat kinase 2 (LRRK2), DJ-1 and Parkin are discussed. Converging mechanisms from different model systems support the concept of common pathways in parkinsonian neurodegeneration that may be amenable to future therapeutic interventions.
"These changes were associated with hypertrophy of glial cells, cell loss in distinct brain regions, and abnormal behavior (Danilovich et al. 2003). Hormonal imbalances in female FORKO mice lead to a disturbed subcellular distribution of activated MAPKs which contribute to the impairments of signal transduction networks maintaining normal physiological functions in the cortex and hippocampus that are associated with neurodegenerative changes in aging (Rumora et al. 2007). We found that FSH and FSH receptor co-located in rat hippocampus, which indicated that FSH might play some important roles in hippocampus by combining with FSH receptor, although we have not known the functions. "
[Show abstract][Hide abstract] ABSTRACT: It has been known that GnRH, LH and their receptors exist in hippocampal neurons. However, whether FSH and its receptor also exist in hippocampal neurons remained unknown yet. In situ hybridization, double-labeled immunofluorescence stain and double-labeled immunohistochemistry stain in adjacent sections were used in our research to study the distribution, co-localization of FSH and its receptor and co-localization of FSH and GnRH receptor in rat hippocampus. The result found that pyramidal neurons from CA1 to CA4 region and granule neurons in dentate gyrus could express FSH and its receptor, majority of hippocampal neurons co-expressed FSH and its receptor, FSH and GnRH receptor. These suggested that hippocampal neurons not only express FSH but also act as FSH target cells. FSH may regulate the function of hippocampal neurons by ways of paracrine or autocrine. At the same time, GnRH may regulate the function of FSH neuron in hippocampus through GnRH receptor.
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