Microglia senescence occurs in both substantia nigra and ventral tegmental area.

During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging-related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1-, 6-, 9-, 18-, and 24-month-old C57BL/J6 mice using sections double-stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, BDNF and TH mRNA were quantified. Results show that the ratio of BDNF to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging-dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging-dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA.

Differential gene expression and stereological analyses of the cerebellum following methamphetamine exposure.

Methamphetamine (METH) is a highly addictive psychostimulant that profoundly aimed at monoaminergic systems in the brain. Despite the leading role of cerebellum in sensorimotor control as well as augmented locomotor activity under the influence of METH, there are few studies examining the effect of METH administration on gene expression profiling and structural consequences in the cerebellar region. Thus, we sought to explore the effects of METH on the cerebellum, from gene expression changes to structural alterations. In this respect, we investigated genome-wide mRNA expression using high throughput RNA-seq technology and confirmatory quantitative real-time PCR, accompanied by stereological analysis of cerebellar layers along with identification of reactive astrogliosis by glial fibrillary acidic protein and behavioral assessment following METH exposure. According to our RNA-seq data, 473 unique differentially expressed genes (DEG) were detected upon METH injections in which a large number of these genes engage basically in biological regulations and metabolic processes, chiefly located in nucleus and membrane. In addition, pathway analysis of METH-induced DEG revealed several enriched signaling cascades related largely to immune response, neurotransmission, cell growth, and death. Further, METH induced a significant reduction in volumes of cerebellar layers (molecular, granular, and Purkinje) and a decrease in the white matter volume along with a rise in astrogliosis as well as increased locomotor activity. In conclusion, considering gene expression changes combined with structural alterations of the cerebellum in response to METH, these data suggest METH-induced neurotoxicity in the cerebellar region.

Prevention of recognition memory loss and moderation of mitochondrial dynamic tendency toward fusion by flavone derivatives in Aß-injected rats: a comparison between two flavonoids with different polarity.

Growing evidence sheds light on the use of flavonoids as the promising alternatives for the treatment of chronic conditions, including cancer and neurodegenerative disorders. Accordingly, in the present study, we aimed at evaluating the effects of oral intake of two structurally different flavonoids 5-hydroxy-6,7,4'-trimethoxyflavone (flavone 1) and 5,7,4'-trihydroxyflavone (flavone 2) on recognition memory, hippocampal protein level of immediate early gene cFos and mitochondrial dynamic markers in Amyloid ß (Aß)-injected rats. Recognition aspect of memory and level of proteins were measured using novel object recognition test and Western blot, respectively. Our data indicated that even though flavone 1 was more effective than flavone 2 to prevent memory impairment, feeding with both flavones alleviated memory in Aß-injected rats. Furthermore, in flavones-administered rats, mitochondrial dynamic balancing returned to the control level by the decline in Dynamin-related protein-1 protein level, a known marker for mitochondrial fission, and elevation in protein level of mitochondrial fusion factors Mitofusins 1 and 2. In parallel with behavior results, flavone 1 was more effectual on mitochondrial dynamic moderating. The more neuroprotective effects of flavone 1 could be attributed to its methylated structure leading to crossing of the blood-brain barrier with ease and metabolic stability and bioactivity.

HIV-1 Tat regulation of dopamine transmission and microglial reactivity is brain region specific.

The transactivator of transcription protein, HIV-1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP-driven Tat protein under doxycycline (Dox) regulation, we investigated microglial-neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for microglia and tyrosine hydroxylase (TH) showed that the ratio of microglia to dopamine neurons is smaller in the SNc than in the ventral tegmental area (VTA) and that this difference is maintained following 7-day Dox exposure in wild type animals. Administration of Dox to wild types had no effect on microglial densities. In addressing the sensitivity of neurons to potentially adverse effects of HIV-1 Tat, we found that HIV-1 Tat exposure in vivo selectively decreased TH immunoreactivity in the SNc but not in the VTA, while levels of TH mRNA in the SNc remained unchanged. HIV-1 Tat induction in vivo did not alter the total number of neurons in these brain regions. Application of Tat (5 ng) into dopamine neurons with whole-cell patch pipette decreased spontaneous firing activity. Tat induction also produced a decline in microglial cell numbers, but no microglial activation. Thus, disappearance of dopaminergic phenotype is due to a loss of TH immunoreactivity rather than to neuronal death, which would have triggered microglial activation. We conclude that adverse effects of HIV-1 Tat produce a hypodopamine state by decreasing TH immunoreactivity and firing activity of dopamine neurons. Reduced microglial numbers after Tat exposure in vivo suggest impaired microglial functions and altered bidirectional interactions between dopamine neurons and microglia.

Methamphetamine neurotoxicity, microglia, and neuroinflammation.

Methamphetamine (METH) is an illicit psychostimulant that is subject to abuse worldwide. While the modulatory effects of METH on dopamine neurotransmission and its neurotoxicity in the central nervous system are well studied, METH's effects on modulating microglial neuroimmune functions and on eliciting neuroinflammation to affect dopaminergic neurotoxicity has attracted considerable attention in recent years. The current review illuminates METH-induced neurotoxicity from a neuropathological perspective by summarizing studies reporting microglial activation after METH administration in rodents. Assessing microglial reactivity in terms of the cells' morphology and immunophenotype offers an opportunity for comprehensive and objective assessment of the severity and nature of METH-induced neuronal perturbations in the CNS and can thus contribute to a better understanding of the nature of METH toxicity. We reach the conclusion here that the intensity of microglial activation reported in the majority of animal models after METH administration is quite modest, indicating that the extent of dopaminergic neuron damage directly caused by this neurotoxicant is relatively minor. Our conclusion stands in contrast to claims of excessive and detrimental neuroinflammation believed to contribute and exacerbate METH neurotoxicity. Thus, our analysis of published studies does not support the idea that suppression of microglial activity with anti-inflammatory agents could yield beneficial effects in terms of treating addiction disorders.

Nitric Oxide and Protein Disulfide Isomerase Explain the Complexities of Unfolded Protein Response Following Intra-hippocampal Aß Injection.

Several pathways involved in regulation of intracellular protein integrity are known as the protein quality control (PQC) system. Molecular chaperones as the main players are engaged in various aspects of PQC system. According to the importance of these proteins in cell survival, in the present study, we traced endoplasmic reticulum-specific markers and chaperone-mediated autophagy (CMA)-associated factors as two main arms of PQC system in intra-hippocampal amyloid beta (Aß)-injected rats during 10 days running. Data analysis from Western blot indicated that exposure to Aß activates immunoglobulin heavy-chain-binding protein (Bip) which is the upstream regulator of unfolded protein responses (UPR). Activation of UPR system eventually led to induction of pro-apoptotic factors like CHOP, calpain, and caspase-12. Moreover, our data revealed that protein disulfide isomerase activity dramatically decreased after Aß injection, which could be attributed to the increased levels of nitric oxide. Besides, Aß injection induced levels of 2 members of heat shock proteins (Hsp) 70 and 90. Elevated levels of Hsps family members are accompanied by increased levels of lysosome-associated membrane protein type-2A (Lamp-2A) that are involved in CMA. Despite the reduction in CHOP, calpain, caspase-12, and Lamp-2A protein levels, the levels of molecular chaperones Bip, Hsps70, and 90 increased 10 days after Aß injection in comparison to the control group. Based on our results, 10 days after Aß injection, despite the activation of protective chaperones, markers associated with neurotoxicity were still elevated.

Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress.

Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap "n" collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II-III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety.

Beneficial Effect of Flavone Derivatives on Aß-Induced Memory Deficit Is Mediated by Peroxisome Proliferator-Activated Receptor γ Coactivator 1α: A Comparative Study.

In the present study, the neuroprotective effect of 5-hydroxy-6,7,4'-trimethoxyflavone (flavone 1), a natural flavone, was investigated in comparison with another flavone, 5,7,4'-trihydroxyflavone (flavone 2) on the hippocampus of amyloid beta (Aß)-injected rats. Rats were treated with the 2 flavones (1 mg/kg/d) for 1 week before Aß injection. Seven days after Aß administration, memory function of rats was assessed in a passive avoidance test (PAT). Changes in the levels of mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), phospho-adenosine monophosphate (AMP)-activated protein kinase (pAMPK), AMPK, phospho-cAMP-responsive element-binding protein (CREB), CREB, and nuclear respiratory factor 1 (NRF-1) proteins were determined by Western blot analysis. Our results showed an improvement in memory in rats pretreated with flavonoids. At the molecular level, phosphorylation of CREB, known as the master modulator of memory processes, increased. On the other hand, the level of mitochondrial biogenesis factors, PGC-1α and its downstream molecules NRF-1 and TFAM significantly increased by dietary administration of 2 flavones. In addition, flavone 1 and flavone 2 prevented mitochondrial swelling and mitochondrial membrane potential reduction. Our results provided evidence that flavone 1 is more effective than flavone 2 presumably due to its O-methylated groups. In conclusion, it seems that in addition to classical antioxidant effect, flavones exert part of their protective effects through mitochondrial biogenesis.

Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer's disease.

3-Methyladenine (3-MA), as a PI3K inhibitor, is widely used for inhibition of autophagy. Inhibition of PI3K class I leads to inhibition of Akt phosphorylation, a central molecule involved in diverse arrays of intracellular cascades in nervous system. Accordingly, in the present study, we aimed to determine the alterations of specific mitochondrial biogenesis markers and mitochondrial function in 3-MA-injected rats following amyloid beta (Aß) insult. Our data revealed that inhibition of Akt phosphorylation downregulates master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our data also showed that decrease in PGC-1α level presumably is due to decrease in the phosphorylation of cAMP-response element binding and AMP-activated kinase, two upstream activators of PGC-1α. As a consequence, the level of some mitochondrial biogenesis factors including nuclear respiratory factor-1, mitochondrial transcription factor A, and Cytochrome c decreased significantly. Also, activities of tricarboxylic acid cycle (TCA) enzymes such as Aconitase, a-ketoglutarate dehydrogenase, and malate dehydrogenase reduced in the presence of 3-MA with or without Aß insult. Decrease in mitochondrial biogenesis factors and TCA enzyme activity in the rats receiving 3-MA and Aß were more compared to the rats that received either alone; indicating the additive destructive effects of these two agents. In agreement with our molecular results, data obtained from behavioral test (using novel objective recognition test) indicated that inhibition of Akt phosphorylation with or without Aß injection impaired novel recognition (non-spatial) memory. Our results suggest that 3-MA amplified deleterious effects of Aß by targeting central molecule Akt.

Enhanced brain delivery of deferasirox-lactoferrin conjugates for iron chelation therapy in neurodegenerative disorders: in vitro and in vivo studies.

Oxidative stress associated cell damage is one of the key factors in neurodegeneration development and is highly related to the presence of transition metal ions including iron. Herein, deferasirox, a high affinity iron chelator, was conjugated to lactoferrin molecules by carbodiimide mediated coupling reaction to create a novel drug delivery system with higher brain permeability through receptor mediated transcytosis. Each lactoferrin molecule was averagely attached to 4 to 6 deferasirox molecules resulting in water-soluble conjugated nanostructures which were purified and characterized. Neuroprotective effects of lactoferrin conjugated nanostructures and their cellular uptake were evaluated in differentiated PC12 cell line, and the molecular mechanisms involved in such neuroprotection were elucidated. Lactoferrin conjugates were able to interfere in apoptotic caspase cascade by affecting the expression level of caspase-3, PARP, Bax and Bcl-2. Furthermore, an elevation in the expression level of autophagy markers including Atg7, Atg12-Atg5 and LC3-II/LC3-I ratio was observed. Intraperitoneal injection of lactoferrin conjugates was able to significantly attenuate learning deficits induced by beta amyloid injection in a rat model of Alzheimer's disease, which further confirms a potential neuroprotective effect for lactoferrin conjugated deferasirox in neurodegenerative disorder management through metal chelation therapy.

Neuroprotective effect of Salvia sahendica is mediated by restoration of mitochondrial function and inhibition of endoplasmic reticulum stress.

Herein, we investigated the protective effect of Salvia sahendica against H(2)O(2)-induced cell death in rat pheochromocytoma (PC12) cells. Our data show that S. sahendica blocks apoptosis pathway by inhibition of cytochrome c release from mitochondria and leakage of calcium from endoplasmic reticulum. It also activates/inactivates two members of Bcl-2 family, Bax and Bcl-2. Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3. Besides S. sahendica suppresses ER stress via attenuation of intracellular levels of calcium. Suppression of ER stress decreased calpain activation and subsequently cleavage of caspase-12. Altogether, these results indicate that S. sahendica protects PC12 cells treated with H(2)O(2) via suppression of upstream factors of apoptosis pathway. While oxidative stress is an early event in Alzheimer disease, it seems that S. sahendica prevents deleterious effects of reactive oxygen species by stabilizing mitochondrial membranes and inhibiting ER stress.

Highlighting the Protective or Degenerative Role of AMPK Activators in Dementia Experimental Models.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR) Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide- 1-ß-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.

Zinc Supplementation During Pregnancy Alleviates Lipopolysaccharide-Induced Glial Activation and Inflammatory Markers Expression in a Rat Model of Maternal Immune Activation.

Maternal immune activation (MIA) model has been profoundly described as a suitable approach to study the pathophysiological mechanisms of neuropsychiatric disorders, including schizophrenia. Our previous study revealed that prenatal exposure to lipopolysaccharide (LPS) induced working memory impairments in only male offspring. Based on the putative role of prefrontal cortex (PFC) in working memory process, the current study was conducted to examine the long-lasting effect of LPS-induced MIA on several neuroinflammatory mediators in the PFC of adult male pups. We also investigated whether maternal zinc supplementation can alleviate LPS-induced alterations in this region. Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on gestation days 15/16 and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy. At postnatal day 60, the density of both microglia and astrocyte cells and the expression levels of IL-6, IL-1ß, iNOS, TNF-α, NF-κB, and GFAP were evaluated in the PFC of male pups. Although maternal LPS treatment increased microglia and astrocyte density, number of neurons in the PFC of adult offspring remained unchanged. These findings were accompanied by the exacerbated mRNA levels of IL-6, IL-1ß, iNOS, TNF-α, NF-κB, and GFAP as well. Conversely, prenatal zinc supplementation alleviated the mentioned alterations induced by LPS. These findings support the idea that the deleterious effects of prenatal LPS exposure could be attenuated by zinc supplementation during pregnancy. It is of interest to suggest early therapeutic intervention as a valuable approach to prevent neurodevelopmental deficits, following maternal infection. Schematic diagram describing the experimental timeline. On gestation days (GD) 15 and 16, pregnant dams were administered with intraperitoneal injections of either LPS (0.5 mg/kg) or vehicle and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy by gavage. The resulting offspring were submitted to qPCR, immunostaining, and morphological analysis at PND 60. Maternal zinc supplementation alleviated increased expression levels of inflammatory mediators and microglia and astrocyte density induced by LPS in the PFC of treated offspring. PND postnatal day, PFC prefrontal cortex.

α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability.

Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson's disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson's disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson's disease progression with significant therapeutic implications.

Early-life stress altered pancreatic Krebs cycle-related enzyme activities in response to young adulthood physical and psychological stress in male rat offspring.

OBJECTIVES: Early-life stress (ELS) increases the risk of metabolic disorders in later life. The present study investigated the ELS effect on pancreatic pyruvate dehydrogenase (PDH) protein level, α-ketoglutarate dehydrogenase (α-KGDH), and aconitase activities as metabolic enzymes in response to young adulthood stress in male rat offspring. METHODS: Male Wistar rats were divided into six groups: Control, early life stress (Early STR), young adult foot-shock stress (Y. adult F-SH STR), early + young adult foot-shock stress (Early + Y. adult F-SH STR), young adult psychological stress (Y. adult Psy STR) and early + young adult psychological stress (Early + Y. adult Psy STR). Stress was induced by a communication box at 2 weeks of age and young adulthood for five consecutive days. The blood samples were collected in young adult rats, then pancreases were removed to measure its PDH protein level and aconitase and α-KGDH activities. RESULTS: In ELS animals, applying foot-shock stress in young adulthood increased PDH protein level, decreased α-KGDH and aconitase activities, and increased plasma glucose, insulin, and corticosterone concentrations. However, exposure to young adulthood psychological stress only decreased α-KGDH and aconitase activities. CONCLUSIONS: It seems that ELS altered metabolic response to young adulthood stress through changes of Krebs cycle-related enzymes activities, though the type of adulthood stress was determinant.

Prenatal zinc supplementation attenuates lipopolysaccharide-induced behavioral impairments in maternal immune activation model.

Maternal infection during pregnancy is considered a key risk factor for developing schizophrenia in offspring. There is evidence that maternal exposure to infectious agents is associated with fetal zinc deficiency. Due to the essential role of zinc in brain function and development, in the present study, we activated maternal immune system using lipopolysaccharide (LPS) as a model of schizophrenia to examine whether zinc supplementation throughout pregnancy can reverse LPS-induced deleterious effects. To test the hypothesis, pregnant rats were treated with intraperitoneal injection of either saline or LPS (0.5 mg/kg) at gestational day 15 and 16, and zinc supplementation (30 mg/kg) was administered throughout pregnancy by gavage. At postnatal day 60, Y-maze was used to evaluate working memory of offspring. Moreover, the expression levels of catechol O-methyltransferase (COMT) and glutamate decarboxylase 67 (GAD67) were measured in the frontal cortex of the brain samples. Only male offspring prenatally exposed to LPS showed a significant impairment in working memory. In addition, prenatal LPS exposure causes a moderate decrease in GAD67 expression level in the male pups, while COMT expression was found unchanged. Interestingly, zinc supplementation restored the alterations in working memory as well as GAD67 mRNA level in the male rats. No alteration was detected for neither working memory nor COMT/GAD67 genes expression in female offspring. This study demonstrates that zinc supplementation during pregnancy can attenuate LPS-induced impairments in male pups. These results support the idea to consume zinc supplementation during pregnancy to limit neurodevelopmental deficits induced by infections in offspring.

Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex.

Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer's disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic reticulum (ER) stress. This study was designed to examine hippocampal ER stress following EC amyloidopathy. Aß1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 µg of isradipine, nimodipine, or placebo over one week. Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus by colorimetric spectrophotometer. Aß treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GSH level in the hippocampus decreased in the Aß treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.

Mitochondrial Aconitase in Neurodegenerative Disorders: Role of a Metabolism- related Molecule in Neurodegeneration.

BACKGROUND: Mitochondrial aconitase (Aco2), a member of the family of iron-sulfur [4Fe- 4S]-containing dehydratases, is involved in cellular metabolism through the tricarboxylic acid cycle. Aco2 is highly susceptible to oxidative damage in a way that exposure to the reactive species and free radicals leads to release of iron from the central [4Fe-4S] cluster resulting in the production of the inactive form of Aco2. OBJECTIVE: There is increasing evidence supporting a direct association between impaired energy metabolism and the incidence and progression of neurodegenerative disorders in neuronal cells. RESULTS: It has been shown that alteration in bioenergetic parameters is a common pathological feature of the neurodegenerative diseases leading to neuronal dysfunction. Numerous studies have demonstrated that dysfunctional Aco2, among the other bioenergetic parameters, is a key factor that could promote neurodegeneration. CONCLUSION: Increasing our knowledge about energy metabolism-related molecules including Aco2 affected by neurodegenerative disorders might be useful to find an efficient therapeutic strategy for those central nervous system-related diseases. Accordingly, in this review, we have focused on the events and processes that occur in neurodegeneration, leading to the inactivation of Aco2 in the brain.

Modulatory role of the intra-accumbal CB1 receptor in protein level of the c-fos and pCREB/CREB ratio in the nucleus accumbens and ventral tegmental area in extinction and morphine seeking in the rats.

Brain reward and motivation circuit begin from the ventral tegmental area (VTA) that its dopaminergic terminals project to various regions of the brain including the nucleus accumbens (NAc). This reward circuit is influenced by drugs of abuse such as morphine and cannabinoid. The present study tried to investigate the role of the intra-accumbal CB1 receptor in the c-fos level and pCREB/CREB ratio in the NAc and the VTA during reinstatement phase of morphine-induced conditioned place preference (CPP) by western blotting. The present data reveals that intra-accumbal administration of CB1 agonist, WIN55,212-2 (0.5, 1 and 2 mM/0.5 µl DMSO) before/during extinction period of morphine-induced CPP, significantly decreased the NAc and the VTA c-fos protein level in the reinstatement phase; whereas the pre-reinstatement administration of the CB1 agonist, increased the c-fos protein level. Intra-accumbal administration of the CB1 agonist during the extinction period of morphine-induced CPP reduced the pCREB/CREB ratio in the NAc. Also, the present data show that intra-accumbal administration of CB1 antagonist, AM251 (15, 45 and 90 µM/0.5 µl DMSO) during/after extinction period of morphine-induced CPP affects the NAc and the VTA c-fos protein level in the reinstatement phase. Also, intra-NAc microinjection of AM251 during the extinction period reduced pCREB/CREB ratio in these regions. In conclusion, the results presented here provide compelling evidence of the modulation and involvement of the c-fos and the CREB molecules in the cannabinoid-opioid interaction of the brain reward system in the CPP paradigm.

Sertoli Cells Avert Neuroinflammation-Induced Cell Death and Improve Motor Function and Striatal Atrophy in Rat Model of Huntington Disease.

Huntington's disease (HD) is a genetically heritable disorder, linked with continuing cell loss and degeneration mostly in the striatum. Currently, cell therapy approaches in HD have essentially been focused on replenishing or shielding cells lost over the period of the disease. Herein, we sought to explore the in vitro and in vivo efficacy of primary rat Sertoli cells (SCs) and their paracrine effect against oxidative stress with emphasis on HD. Initially, SCs were isolated and immunophenotypically characterized by positive expression of GATA4. Besides, synthesis of neurotrophic factors of glial cell-derived neurotrophic factor and VEGF by SCs were proved. Next, PC12 cells were exposed to hydrogen peroxide in the presence of conditioned media (CM) collected from SC (SC-CM) and cell viability and neuritogenesis were determined. Bilateral striatal implantation of SC in 3-nitropropionic acid (3-NP)-lesioned rat models was performed, and 1 month later, post-graft analysis was done. According to our in vitro results, the CM of SC protected PC12 cells against oxidative stress and remarkably augmented cell viability and neurite outgrowth. Moreover, grafted SCs survived, exhibited decreases in both gliosis and inflammatory cytokine levels, and ameliorated motor coordination and muscle activity, together with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. In conclusion, our results indicate that SCs provide a supportive environment, with potential therapeutic benefits aimed at HD.