Dose-dependent Effects of Ladostigil on Microglial Activation and Cognition in Aged Rats

Weinstock, Marta; Bejar, Corina; Schorer-Apelbaum, Donna; Panarsky, Rony; Luques, Lisandro; Shoham, Shai

doi:10.1007/s11481-013-9433-0

Cited by 17 publications

(11 citation statements)

References 67 publications

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“…The reason for the failure of the control animals to explore the novel object is not clear. While previous research has shown that older rats explore less than younger rats [17] [18], this cannot account for the present Summary of the effects of exposure to HZE particles and protons on the on the dose needed to disrupt object recognition performance on the first (young) and second test (old). The data is presented as log of threshold dose: the dose needed to produce a significant disruption of object recognition memory.…”

Section: Discussioncontrasting

confidence: 68%

Effects of Age on the Disruption of Cognitive Performance by Exposure to Space Radiation

Rabin¹,

Shukitt‐Hale²,

Carrihill-Knoll³

2014

JBBS

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Exposure to low doses of heavy particles and protons, which will be encountered during long-term exploratory class missions to other planets, can cause deficits in cognitive performance. These deficits are similar to those observed in aged animals. The long-term effects of such exposures and their relationship to the short-term effects and to aging remain to be established. Two-month old rats were exposed to a variety of heavy particles and protons. Recognition memory was tested at two time points following irradiation. The results showed that exposure to doses of radiation that did not disrupt cognitive performance in the younger animals, disrupted performance when the subjects were re-tested at an older age. These results indicate that there is an interaction between the age of the organism and the effects of exposure to space radiation on cognitive performance, such that exposure to doses of heavy particles or protons that may not produce an initial effect on cognitive performance may produce an effect as the organism ages. Because of the interaction between exposure to the types of radiation encountered in space and age, it is possible that participating in exploratory class missions may have consequences for the quality of life after the conclusion of the mission.

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Section: Discussioncontrasting

confidence: 68%

Effects of Age on the Disruption of Cognitive Performance by Exposure to Space Radiation

Rabin¹,

Shukitt‐Hale²,

Carrihill-Knoll³

2014

JBBS

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“…Experiments were performed as previously described, and the interaction by the rats with the objects was videotaped [54]. Since the prepubertal rats were very active, an observation period of 1 min was sufficient to enable the detection of NOR.…”

Section: Methodsmentioning

confidence: 99%

“…Reference memory was assessed in the Morris water maze (MWM) as described previously [54] in 9-10 rats of each sex and prenatal treatment. The rats were given 2 trials a day for 4 days between 10.00 and 14.00 h with an ITI of 30-40 min.…”

Section: Methodsmentioning

confidence: 99%

Sex-Specific Effects of Prenatal Stress on Memory and Markers of Neuronal Activity in Juvenile Rats

Barbie-Shoshani

Shoham²,

Bejar³

et al. 2016

Dev Neurosci

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Stress during pregnancy can increase the incidence of emotional problems, learning and language difficulties in human infants and pre-adolescents. Most preclinical studies in rats that attempted to find experimental support for these observations were performed in adult male offspring, but the results are inconsistent. The aim of the current study was to examine the effect of prenatal stress on novel object recognition (NOR) and spatial learning and memory in the Morris water maze (MWM) of juvenile rats of both sexes. By the use of fluorescence immunohistochemistry and protein measurements by Western blot, we measured the expression of markers of neurogenesis (doublecortin, DCX) and neuronal activity that are important for synaptic plasticity and learning (c-fos, GluR1, nNOS). Since neuronal activity in the developing and adult brain can be regulated by astrocytes, we also measured the number of astrocytes and the expression of two astroglial proteins (GFAP and S100B) in the stress-responsive hippocampal dentate gyrus (DG). Experiments were performed on littermates of rats in which its effects on behavior were measured. We found for the first time that juvenile females performed better than males in the NOR and MWM tests. They also had higher densities of DCX and c-fos in the DG, together with the expression of nNOS and GluR1 in the subgranular zone (SGZ) of the DG. There were no sex differences in the expression of GFAP and S100B in astrocytes. Prenatal stress did not affect NOR in females, but improved it in males, together with an increase in DCX+ and c-fos, the number of GFAP-expressing astrocytes and the intensity of GFAP and S100B immunofluorescence in the DG. Staining intensity of GluR1 and nNOS in the hilus and SGZ of the DG, and protein expression in the whole DG, was unchanged in prenatally stressed males. Thus, prenatal stress changed the behavior and expression of key proteins in the DG to resemble that in females. A reduction in plasma testosterone, which although not attaining statistical significance was associated with that in anogenital distance, may contribute to the effect of prenatal stress in males. In females, prenatal stress had no effect on c-fos, DCX or the number of astrocytes but reduced the staining intensity of GluR1 and nNOS. Protein expression of nNOS was also significantly lower than that in prenatally stressed males. The differential effects of prenatal stress on hippocampal neuronal and glial markers may help to explain the sex-dependent effect on spatial learning in prepubertal rats.

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“…Regarding the effect of ladostigil on age‐related alterations, previous in vivo studies demonstrated that the drug improved cognitive deficits in aged monkeys (Buccafusco et al ., ) and prevented the development of age‐related memory deficits in aged rats (Weinstock et al ., ; Panarsky et al ., ; Weinstock et al ., ) (Table ). These beneficial effects may be associated with immunomodulatory (microglial activation) and antioxidant effects of ladostigil (Weinreb et al ., ; Weinstock et al ., ). In agreement with this hypothesis, aged rats treated with ladostigil showed an increase in pro‐NGF in various brain regions, presumably resulting from enhanced neuronal activity (Weinstock et al ., ).…”

Section: The Che and Mao Inhibitory Compound Ladostigilmentioning

confidence: 99%

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Weinreb

Amit

Bar-Am

et al. 2015

British J Pharmacology

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Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the

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Dose-dependent Effects of Ladostigil on Microglial Activation and Cognition in Aged Rats

Abstract: Ladostigil (1 mg/kg/day) prevents the development of age-related memory deficits by a combination of immunomodulatory and antioxidant effects. A dose causing 30 % ChE inhibition is necessary in order to reverse existing memory deficits at 20 months of age.

Cited by 17 publications

References 67 publications

Effects of Age on the Disruption of Cognitive Performance by Exposure to Space Radiation

Effects of Age on the Disruption of Cognitive Performance by Exposure to Space Radiation

Sex-Specific Effects of Prenatal Stress on Memory and Markers of Neuronal Activity in Juvenile Rats

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

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