Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats

Aglawe, Manish M.; Kale, Mayur B.; Rahangdale, Sandip R.; Kotagale, Nandkishor R.; Umekar, Milind J.; Taksande, Brijesh G.

doi:10.1016/j.brainresbull.2020.11.015

Cited by 26 publications

(16 citation statements)

References 76 publications

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“…Earlier studies have established that agmatine can exert both antidepressant and anxiolytic effects in various rodent models, including the unpredictable mild stress model (Aricioglu & Altunbas, 2003; Kale et al, 2020; Moretti et al, 2015; Ozkartal et al, 2019; Zomkowski et al, 2002). Furthermore, a recent study has shown that chronic postnatal administration of agmatine improves the behavioural and cognitive deficits related to chronic gestational ethanol exposure in the offspring (Aglawe et al, 2021). However, to the best of our knowledge, this is the first study demonstrating the anxiolytic and antidepressive effects of prenatally administered agmatine on PS offspring, suggesting that agmatine is not only protective postnatally but also during the prenatal developmental period.…”

Section: Discussionmentioning

confidence: 99%

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring

Hassanshahi

Janahmadi

Razavinasab

et al. 2023

Intl J of Devlp Neuroscience

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Physical or psychological stress experienced by a mother during gestation is often associated with serious behavioural and cognitive deficits in newborns. Investigations of protective agents, which could prevent the adverse outcomes of prenatal stress (PS), are warranted. Agmatine is a neurotransmitter putatively involved in the physiological response to stress, and exogenous administration of agmatine has been shown to produce a variety of neuroprotective effects. In this study, we aimed to assess whether prenatal agmatine exposure could ameliorate behavioural and cognitive deficits in female offspring born to prenatally stressed mice. Pregnant Swiss Webster (SW) mice were exposed to physical or psychological stress from the 11th to 17th days of gestation. Agmatine (37.5 mg/kg, i.p.) was administrated 30 min before the induction of stress for seven consecutive days. The pups were assessed using a variety of behavioural tests and molecular assays on postnatal days 40 to 47. Agmatine attenuated impairments in locomotor activity, anxiety‐like behaviour, and drug‐seeking behaviour associated with both physical and psychological PS. Furthermore, agmatine reduced PS‐induced impairments in passive avoidance memory and learning. Neither PS nor agmatine treatment affected the mRNA expression level of hippocampal brain‐derived neurotrophic factor (BDNF) or tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). Taken together, our findings highlight the protective effects of prenatally administered agmatine on PS‐mediated behavioural and cognitive deficits of the offspring. Future studies are needed to elucidate the underlying mechanisms, which could allow for more targeted prenatal treatments.

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Section: Discussionmentioning

confidence: 99%

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring

Hassanshahi

Janahmadi

Razavinasab

et al. 2023

Intl J of Devlp Neuroscience

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“…Similar observations were found in previous studies based on acute early gestational ethanol exposure [ 50 , 51 , 66 , 88 ]. In contrast, chronic ethanol exposure throughout the gestational period has been shown to reduce pup or offspring body weight [ 89 , 90 ]. In the prenatal stage (GD13.5), GDE exposure induced cell death and reduced cell differentiation and cell survival signaling (pERK and pCREB).…”

Section: Discussionmentioning

confidence: 99%

Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice

Subbanna

Basavarajappa

2022

Brain Sciences

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An embryo’s in-utero exposure to ethanol due to a mother’s alcohol drinking results in a range of deficits in the child that are collectively termed fetal alcohol spectrum disorders (FASDs). Prenatal ethanol exposure is one of the leading causes of preventable intellectual disability. Its neurobehavioral underpinnings warrant systematic research. We investigated the immediate effects on embryos of acute prenatal ethanol exposure during gestational days (GDs) and the influence of such exposure on persistent neurobehavioral deficits in adult offspring. We administered pregnant C57BL/6J mice with ethanol (1.75 g/kg) (GDE) or saline (GDS) intraperitoneally (i.p.) at 0 h and again at 2 h intervals on GD 8 and GD 12. Subsequently, we assessed apoptosis, differentiation, and signaling events in embryo forebrains (E13.5; GD13.5). Long-lasting effects of GDE were evaluated via a behavioral test battery. We also determined the long-term potentiation and synaptic plasticity-related protein expression in adult hippocampal tissue. GDE caused apoptosis, inhibited differentiation, and reduced pERK and pCREB signaling and the expression of transcription factors Pax6 and Lhx2. GDE caused persistent spatial and social investigation memory deficits compared with saline controls, regardless of sex. Interestingly, GDE adult mice exhibited enhanced repetitive and anxiety-like behavior, irrespective of sex. GDE reduced synaptic plasticity-related protein expression and caused hippocampal synaptic plasticity (LTP and LTD) deficits in adult offspring. These findings demonstrate that binge-like ethanol exposure at the GD8 and GD12 developmental stages causes defects in pERK–pCREB signaling and reduces the expression of Pax6 and Lhx2, leading to impaired cellular differentiation during the embryonic stage. In the adult stage, binge-like ethanol exposure caused persistent synaptic and behavioral abnormalities in adult mice. Furthermore, the findings suggest that combining ethanol exposure at two sensitive stages (GD8 and GD12) causes deficits in synaptic plasticity-associated proteins (Arc, Egr1, Fgf1, GluR1, and GluN1), leading to persistent FASD-like neurobehavioral deficits in mice.

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“…An interesting recent study evaluated the pharmacological effects of treating agmatine on the offspring of rats exposed to alcohol in the prenatal period. The results showed potential for treating cognitive impairment and other neurological complications associated with fetal alcohol spectrum disorders (Aglawe et al, 2021). Agmatine has also been shown to have significant hepatic and renal protective functions in cholestatic animals.…”

Section: Introductionmentioning

confidence: 89%

Improving the Stability and Activity of Arginine Decarboxylase at Alkaline pH for the Production of Agmatine

et al. 2021

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Agmatine, involved in various modulatory actions in cellular mechanisms, is produced from arginine (Arg) by decarboxylation reaction using arginine decarboxylase (ADC, EC 4.1.1.19). The major obstacle of using wild-type Escherichia coli ADC (ADCes) in agmatine production is its sharp activity loss and instability at alkaline pH. Here, to overcome this problem, a new disulfide bond was rationally introduced in the decameric interface region of the enzyme. Among the mutants generated, W16C/D43C increased both thermostability and activity. The half-life (T1/2) of W16C/D43C at pH 8.0 and 60°C was 560 min, which was 280-fold longer than that of the wild-type, and the specific activity at pH 8.0 also increased 2.1-fold. Site-saturation mutagenesis was subsequently performed at the active site residues of ADCes using the disulfide-bond mutant (W16C/D43C) as a template. The best variant W16C/D43C/I258A displayed a 4.4-fold increase in the catalytic efficiency when compared with the wild-type. The final mutant (W16C/D43C/I258A) was successfully applied to in vitro synthesis of agmatine with an improved yield and productivity (>89.0% yield based on 100 mM of Arg within 5 h).

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Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats

Cited by 26 publications

References 76 publications

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring

Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice

Improving the Stability and Activity of Arginine Decarboxylase at Alkaline pH for the Production of Agmatine

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