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Treatment with melatonin is routinely prescribed for its potent antioxidant and cognitive‐promoting effects, nevertheless, it has yet to find neuromodulatory effects in normal and disease conditions. Therefore, to investigate its neuromodulatory mechanisms, melatonin was systemically administered over 10 consecutive days to both intracortical normal saline‐ and amyloid‐β 1‐42 (Aβ) peptide‐injected rats. At the behavioral level, treatment with melatonin was associated with reduced efficacy in restoring Aβ‐induced deficit in passive‐avoidance memory. Whole‐cell patch‐clamp recordings from CA1 pyramidal neurons revealed that melatonin treatment reduced spontaneous and evoked intrinsic excitability in control rats while exerting a reduction of spontaneous, but not evoked activity, in the Aβ‐injected group. Interestingly, treatment with melatonin enhances after‐hyperpolarization in control, but not Aβ‐injected rats. In contrast, our voltage‐clamp study showed that Ih current is significantly enhanced by Aβ injection, and this effect is further strengthened by treatment with melatonin in Aβ‐injected rats. Finally, we discovered that the transcription of melatonin receptors 1 (MT1) and 2 (MT2) is significantly upregulated in the hippocampi of Aβ‐injected rats. Collectively, our study demonstrates that systemic treatment with melatonin has differential neuromodulation on CA1 neuronal excitability, at least in part, via differential effects on after‐hyperpolarization and Ih currents due to Aβ‐induced neurotoxicity. Summary: The molecular and cellular underpinnings of AD pathology are accompanied by developing aberrant neuronal excitability. These neuronal properties are also a part of melatonin effectors by which melatonin exerts its cognitive‐promoting and anti‐seizure effects. In this paper, we answer the question of how melatonin may influence neuronal excitability in healthy and AD‐like conditions. Answering this query is important considering the fact that melatonin effectiveness is altered with the development of AD. This may be due to, as we demonstrate, the deregulation of melatonin receptors in the hippocampus of AD rats. These findings are significant because shed further light on the cellular mechanisms of melatonin and help us to understand AD pathophysiology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ25−35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ25−35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ25−35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aβ25−35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ25−35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD. [ABSTRACT FROM AUTHOR]

Prenatal stress (PS) results from a maternal experience of stressful events during pregnancy, which has been associated with an increased risk of behavioral disorders including substance abuse and anxiety in the offspring. PS is known to result in heightened dopamine release in the ventral tegmental area (VTA), in part through the effects of corticotropin‐releasing hormone, which directly excites dopaminergic cells. It has recently been suggested that agmatine plays a role in modulating anxiety‐like behaviors. In this study, we investigated whether agmatine could reduce negative cognitive outcomes in male mice prenatally exposed to psychological/physical stress, and whether this could be associated with molecular changes in VTA. Agmatine (37.5 mg/kg) was administrated 30 min prior to PS induction in pregnant Swiss mice. Male offspring were evaluated in a series of behavioral and molecular assays. Findings demonstrated that agmatine reduced the impairment in locomotor activity induced by both psychological and physical PS. Agmatine also decreased heightened conditioned place preference to morphine seen in PS offspring. Moreover, agmatine ameliorated the anxiety‐like behavior and drug‐seeking behavior induced by PS in the male offspring. Molecular effects were seen in VTA as the enhanced brain‐derived neurotrophic factor (BDNF) induced by PS in the VTA was reduced by agmatine. Behavioral tests indicate that agmatine exerts a protective effect on PS‐induced impairments in male offspring, which could be due in part to agmatine‐associated molecular alterations in the VTA. Taken together, our data suggest that prenatal treatment with agmatine exerts protective effect against negative consequences of PS on the development of affective circuits in the offspring. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]