Antitumor Effects of an Anthocyanin-Rich Grain Diet in a Mouse Model of Lewis Lung Carcinoma.

Functional foods enriched with plant polyphenol anthocyanins attract particular attention due to their health-promoting properties, including antitumor activity. We evaluated the effects of a grain diet rich in anthocyanins in a mouse model of Lewis lung carcinoma. Mice of the C57BL/6 strain were fed with wheat of near-isogenic lines differing in the anthocyanin content for four months prior to tumor transplantation. Although a significant decrease in the size of the tumor and the number of metastases in the lungs was revealed in the groups with both types of grain diet, the highest percentage of animals without metastases and with attenuated cell proliferation in the primary tumor were observed in the mice with the anthocyanin-rich diet. Both grain diets reduced the body weight gain and spleen weight index. The antitumor effects of the grain diets were associated with the activation of different mechanisms: immune response of the allergic type with augmented interleukin(IL)-9 and eotaxin serum levels in mice fed with control grain vs. inhibition of the IL-6/LIF system accompanied by a decrease in the tumor-associated M2 macrophage marker arginase 1 gene mRNA levels and enhanced autophagy in the tumor evaluated by the mRNA levels of Beclin 1 gene. Thus, anthocyanin-rich wheat is suggested as a promising source of functional nutrition with confirmed in vivo antitumor activity.

Comparative analysis of early neurodegeneration signs in a mouse model of Alzheimer's disease-like pathology induced by two types of the central (Intracerebroventricular vs. Intrahippocampal) administration of Aß25-35 oligomers.

Animal models of Alzheimer's disease (AD) induced by intracerebroventricular (ICV) or intrahippocampal (IH) administration of amyloid-beta (Aß) are widely used in current research. It remains unclear whether these models provide similar outcomes or mimic pathological mechanisms of AD equally. The aim of the work was to compare two models induced by ICV or IH administration of Aß25-35 oligomers to C57BL/6 mice. Parameters characterizing cognitive function (passive avoidance test), protein expression (IBA1, Aß, LC3-II) and expression of genes for neuroinflammation (Aif1, Lcn2, Nrf2), autophagy (Atg8, Becn1, Park2), or markers of neurodegeneration (Cst3, Insr, Vegfa) were analyzed. Сognitive deficits, amyloid accumulation, and neuroinflammatory response in the brain evaluated by the microglial activation were similar in both models. Thus, both ways of Aß administration appear to be equally suitable for modelling AD-like pathology in mice. Our findings strongly support the key role of Aß load and neuroinflammatory response in the hippocampus and frontal cortex for the progression of AD-like pathology and development of cognitive deficits. There were certain minor differences between the models in the mRNA level of genes involved in the processes of neuroinflammation, neurodegeneration, and autophagy. Modulating effects of the central administration of Aß25-35 on the mRNA expression of Aif1, Lcn2, Park2, and Vegfa genes in different brain structures were revealed. The effects occurred to be more pronounced with the ICV method compared with the IH method. These findings give insight into the processes at initial stages of Aß-induced pathology depending on a primary location of Aß oligomers in the brain.

Brain but not serum BDNF levels are associated with structural alterations in the hippocampal regions in patients with drug-resistant mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy is the most common type of focal epilepsy, imposing a significant burden on the health care system worldwide. Approximately one-third of patients with this disease who do not adequately respond to pharmacotherapy are considered drug-resistant subjects. Despite having some clues of how such epileptic activity and resistance to therapy emerge, coming mainly from preclinical models, we still witness a scarcity of human data. To narrow this gap, in this study, we aimed to estimate the relationship between hippocampal and serum levels of brain-derived neurotrophic factor (BDNF), one of the main and most widely studied neurotrophins, and hippocampal subfield volumes in patients with drug-resistant mesial temporal epilepsy undergoing neurosurgical treatment. We found that hippocampal (but not serum) BDNF levels were negatively correlated with the contralateral volumes of the CA1 and CA4 subfields, presubiculum, subiculum, dentate gyrus, and molecular layer of the hippocampus. Taken together, these findings are generally in accordance with existing data, arguing for a proepileptic nature of BDNF effects in the hippocampus and related brain structures.

Concordance between the In Vivo Content of Neurospecific Proteins (BDNF, NSE, VILIP-1, S100B) in the Hippocampus and Blood in Patients with Epilepsy.

The identification of reliable brain-specific biomarkers in periphery contributes to better understanding of normal neurophysiology and neuropsychiatric diseases. The neurospecific proteins BDNF, NSE, VILIP-1, and S100B play an important role in the pathogenesis of neuropsychiatric disorders, including epilepsy. This study aimed to assess the correspondence of the expression of BDNF, NSE, VILIP-1, and S100B in the blood (serum and peripheral blood mononuclear cells (PBMCs)) to the in vivo hippocampal levels of subjects with drug-resistant epilepsy who underwent neurosurgery (N = 44) using multiplex solid-phase analysis, ELISA, and immunohistochemical methods, as well as to analyze the correlations and associations of the blood and hippocampal levels of these proteins with clinical parameters. We first studied the concordance between in vivo brain and blood levels of BDNF, NSE, VILIP-1, and S100B in epileptic patients. A positive correlation for NSE between hippocampal and PBMC levels was revealed. NSE levels in PBMCs were also significantly correlated with average seizure duration. BDNF levels in PBMCs were associated with seizure frequency and hippocampal sclerosis. Thus, NSE and BDNF levels in PBMCs may have potential as clinically significant biomarkers. Significant correlations between the levels of the neurospecific proteins studied herein suggest interactions between BDNF, NSE, VILIP-1, and S100B in the pathophysiology of epilepsy.

Flavonoids as Promising Neuroprotectants and Their Therapeutic Potential against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the serious and progressive neurodegenerative disorders in the elderly worldwide. Various genetic, environmental, and lifestyle factors are associated with its pathogenesis that affect neuronal cells to degenerate over the period of time. AD is characterized by cognitive dysfunctions, behavioural disability, and psychological impairments due to the accumulation of amyloid beta (Aß) peptides and neurofibrillary tangles (NFT). Several research reports have shown that flavonoids are the polyphenolic compounds that significantly improve cognitive functions and inhibit or delay the amyloid beta aggregation or NFT formation in AD. Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems including AD. During AD pathogenesis, multiple signalling pathways are involved and to target a single pathway may relieve the symptoms but not provides the permanent cure. Flavonoids communicate with different signalling pathways and adjust their activities, accordingly prompting valuable neuroprotective impacts. Flavonoids likewise hamper the movement of obsessive indications of neurodegenerative disorders by hindering neuronal apoptosis incited by neurotoxic substances. In this short review, we briefly discussed about the classification of flavonoids and their neuroprotective properties that could be used as a potential source for the treatment of AD. In this review, we also highlight the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production.

A Novel Laser-Based Zebrafish Model for Studying Traumatic Brain Injury and Its Molecular Targets.

Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate potential targets for neuroreparative treatment. Overall, TBI induced hypolocomotion and anxiety-like behavior in the novel tank test, strikingly recapitulating responses in mammalian TBI models, hence supporting the face validity of our model. NeuN-positive cell staining was markedly reduced one day, but not seven days, after TBI, suggesting increased neuronal damage immediately after the injury, and its fast recovery. The brain-derived neurotrophic factor (Bdnf) level in the brain dropped immediately after the trauma, but fully recovered seven days later. A marker of microglial activation, Iba1, was elevated in the TBI brain, albeit decreasing from Day 3. The levels of hypoxia-inducible factor 1-alpha (Hif1a) increased 30 min after the injury, and recovered by Day 7, further supporting the construct validity of the model. Collectively, these findings suggest that our model of laser-induced brain injury in zebrafish reproduces mild TBI and can be a useful tool for TBI research and preclinical neuroprotective drug screening.

Neurospecific Molecules Measured in Periphery in Humans: How Do They Correlate with the Brain Levels? A Systematic Review.

Human brain state is usually estimated by brain-specific substances in peripheral tissues, but, for most analytes, a concordance between their content in the brain and periphery is unclear. In this systematic review, we summarized the investigated correlations in humans. PubMed was searched up to June 2022. We included studies measuring the same endogenous neurospecific analytes in the central nervous system and periphery in the same subjects. Not eligible were studies of cerebrospinal fluid, with significant blood-brain barrier disruption, of molecules with well-established blood-periphery concordance or measured in brain tumors. Seventeen studies were eligible. Four studies did not report on correlation and four revealed no significant correlation. Four molecules were examined twice. For BDNF, there was no correlation in both studies. For phenylalanine, glutamine, and glutamate, results were contradictory. Strong correlations were found for free tryptophan (r = 0.97) and translocator protein (r = 0.90). Thus, only for three molecules was there some certainty. BDNF in plasma or serum does not reflect brain content, whereas free tryptophan (in plasma) and translocator protein (in blood cells) can serve as peripheral biomarkers. We expect a breakthrough in the field with advanced in vivo metabolomic analyses, neuroimaging techniques, and blood assays for exosomes of brain origin.

Structural and functional characteristics of the hippocampus in depressive-like recipients after transplantation of in vitro caffeine-modulated immune cells.

The hippocampus is a key anatomical brain region associated with depression. On the other hand, immune cells and their releasing cytokines play an essential role in stress and depression. Noteworthy that the most of psychoactive drugs produce unidirectional effects on the cells of both nervous and immune systems. This suggests the immunotherapy for behavioral disorders based on the treatment with autologous immune cells in which functional activity was modulated ex vivo by a psychoactive drug. Here, we treated the immune cells of depressive-like mice in vitro with caffeine (100 µg per 15 × 106 cells). The effects of caffeine-treated immune cells transplantation on neuronal density, production of brain-derived neurotrophic factor (BDNF) and a number of cytokines in the hippocampus of depressive-like syngeneic animals were studied. In depressive-like recipients, an increase in the density of pyramidal neurons in CA1 and CA3 hippocampal regions, accompanied with augmented level of BDNF, decreased levels of pro-inflammatory (IL-1ß, IL-6, INF-γ, and TNF-α) and increased levels of anti-inflammatory (IL-10 and IL-4) cytokines was found. The mechanisms of the revealed structural and functional alterations in the hippocampus of depressive-like recipients after transplantation of caffeine-treated immune cells are discussed.

Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential.

Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.

Combined induction of mTOR-dependent and mTOR-independent pathways of autophagy activation as an experimental therapy for Alzheimer's disease-like pathology in a mouse model.

Alzheimer's disease (AD) is associated with amyloid-ß (Aß) accumulation that might be hindered by autophagy. There are two ways to induce autophagy: through mTOR-dependent and mTOR-independent pathways (here, by means of rapamycin and trehalose, respectively). The aim of this study was to evaluate the contribution of these pathways and their combination to the treatment of experimental AD. Mice were injected bilaterally intracerebroventricularly with an Aß fragment (25-35) to set up an AD model. Treatment with rapamycin (10 mg/kg, every other day), trehalose consumption with drinking water (2 mg/mL, ad libitum), or their combination started 2 days after the surgery and lasted for 2 weeks. Open-field, plus-maze, and passive avoidance tests were used for behavioral phenotyping. Neuronal density, Aß accumulation, and the expression of autophagy marker LC3-II and neuroinflammatory marker IBA1 were measured in the frontal cortex and hippocampus. mRNA levels of autophagy genes (Atg8, Becn1, and Park2) were assessed in the hippocampus. Trehalose but not rapamycin caused pronounced prolonged autophagy induction and transcriptional activation of autophagy genes. Both drugs effectively prevented Aß deposition and microglia activation. Autophagy inhibitor 3-methyladenine significantly attenuated autophagy activation and disturbed the effect of the inducers on Aß load. The inducers substantially reversed behavioral and neuronal deficits in Aß-injected mice. In many cases, the best outcomes were achieved with the combined treatment. Thus, trehalose alone or combined autophagy activation by the two inducers may be a promising treatment approach to AD-like neurodegeneration. Some aspects of interaction between mTOR-dependent and mTOR-independent pathways of autophagy are discussed.

Modeling neurodegenerative disorders in zebrafish.

Neurodegeneration is a major cause of Alzheimer's, Parkinson's, Huntington's, multiple and amyotrophic lateral sclerosis, pontocerebellar hypoplasia, dementia and other related brain disorders. Their complex pathogenesis commonly includes genetic and neurochemical deficits, misfolded protein toxicity, demyelination, apoptosis and mitochondrial dysfunctions. Albeit differing in specific underlying mechanisms, neurodegenerative disorders typically display evolutionarily conserved mechanisms across taxa. Here, we review the role of zebrafish models in recapitulating major human and rodent neurodegenerative conditions, demonstrating this species as a highly relevant experimental model for research on neurodegenerative diseases, and discussing how these fish models can further clarify the underlying genetic, neurochemical, neuroanatomical and behavioral pathogenic mechanisms.

Copper-mediated ß-amyloid toxicity and its chelation therapy in Alzheimer's disease.

The link between bio-metals, Alzheimer's disease (AD), and its associated protein, amyloid-ß (Aß), is very complex and one of the most studied aspects currently. Alzheimer's disease, a progressive neurodegenerative disease, is proposed to occurs due to the misfolding and aggregation of Aß. Dyshomeostasis of metal ions and their interaction with Aß has largely been implicated in AD. Copper plays a crucial role in amyloid-ß toxicity, and AD development potentially occurs through direct interaction with the copper-binding motif of APP and different amino acid residues of Aß. Previous reports suggest that high levels of copper accumulation in the AD brain result in modulation of toxic Aß peptide levels, implicating the role of copper in the pathophysiology of AD. In this review, we explore the possible mode of copper ion interaction with Aß, which accelerates the kinetics of fibril formation and promote amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of various copper chelators in the prevention of copper-mediated Aß toxicity. KEYWORDS: Short Twitter Statement: Authors explore copper ion interaction w/ Aß and kinetics of fibril formation in promoting amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of copper chelators in the prevention of copper-mediated Aß toxicity. SHORT TWITTER STATEMENT: Authors explore copper ion interaction w/Aß and kinetics of fibril formation in promoting amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of copper chelators in the prevention of copper-mediated Aß toxicity.

Chronic Administration of 7,8-DHF Lessens the Depression-like Behavior of Juvenile Mild Traumatic Brain Injury Treated Rats at Their Adult Age.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe TBI as it occurs in adults. This study explored the long-term adverse effect of mild TBI in juvenile animals (mTBI-J). Male Sprague Dawley rats received mTBI-J or sham treatment at six weeks old, then underwent behavioral, biochemical, and histological experiments three weeks later (at nine weeks old). TTC staining, H&E staining, and brain edema measurement were applied to evaluate the mTBI-J induced cerebral damage. The forced swimming test (FST) and sucrose preference test (SPT) were applied for measuring depression-like behavior. The locomotor activity test (LAT) was performed to examine mTBI-J treatment effects on motor function. After the behavioral experiments, the dorsal hippocampus (dHip) and ventral hippocampus (vHip) were dissected out for western blotting to examine the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). Finally, a TrkB agonist 7,8-DHF was injected intraperitoneally to evaluate its therapeutic effect on the mTBI-J induced behavioral abnormalities at the early adult age. Results showed that a mild brain edema occurred, but no significant neural damage was found in the mTBI-J treated animals. In addition, a significant increase of depression-like behaviors was observed in the mTBI-J treated animals; the FST revealed an increase in immobility, and a decrease in sucrose consumption was found in the mTBI-J treated animals. There were no differences observed in the total distance traveled of the LAT and the fall latency of the rotarod test. The hippocampal BDNF expression, but not the TrkB, were significantly reduced in mTBI-J, and the mTBI-J treatment-induced depression-like behavior was lessened after four weeks of 7,8-DHF administration. Collectively, these results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which raises the depression-like behavior in the adult age. In addition, chronic administration of 7,8-DHF lessens the mTBI-J treatment-induced depression-like behaviors in adult rats. We suggest the potential usage of 7,8-DHF as a therapeutic agent for preventing the long-term adverse effect of mTBI-J.

Neuroprotective Effects of Ceftriaxone Involve the Reduction of Aß Burden and Neuroinflammatory Response in a Mouse Model of Alzheimer's Disease.

Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer's disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aß) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aß deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aß. Mice were injected bilaterally i.c.v. with Aß fragment 25-35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aß neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

Treatment with Autophagy Inducer Trehalose Alleviates Memory and Behavioral Impairments and Neuroinflammatory Brain Processes in db/db Mice.

Autophagy attenuation has been found in neurodegenerative diseases, aging, diabetes mellitus, and atherosclerosis. In experimental models of neurodegenerative diseases, the correction of autophagy in the brain reverses neuronal and behavioral deficits and hence seems to be a promising therapy for neuropathologies. Our aim was to study the effect of an autophagy inducer, trehalose, on brain autophagy and behavior in a genetic model of diabetes with signs of neuronal damage (db/db mice). A 2% trehalose solution was administered as drinking water during 24 days of the experiment. Expressions of markers of autophagy (LC3-II), neuroinflammation (IBA1), redox state (NOS), and neuronal density (NeuN) in the brain were assessed by immunohistochemical analysis. For behavioral phenotyping, the open field, elevated plus-maze, tail suspension, pre-pulse inhibition, and passive avoidance tests were used. Trehalose caused a slight reduction in increased blood glucose concentration, considerable autophagy activation, and a decrease in the neuroinflammatory response in the brain along with improvements of exploration, locomotor activity, anxiety, depressive-like behavior, and fear learning and memory in db/db mice. Trehalose exerted some beneficial peripheral and systemic effects and partially reversed behavioral alterations in db/db mice. Thus, trehalose as an inducer of mTOR-independent autophagy is effective at alleviating neuronal and behavioral disturbances accompanying experimental diabetes.

Evaluating the Effects of Grain of Isogenic Wheat Lines Differing in the Content of Anthocyanins in Mouse Models of Neurodegenerative Disorders.

Functional foods enriched with plant polyphenols and anthocyanins in particular attract special attention due to multiple beneficial bioactive properties of the latter. We evaluated the effects of a grain diet rich in anthocyanins in a mouse model of Alzheimer's disease induced by amyloid-beta (Aß) and a transgenic mouse model of Parkinson's disease (PD) with overexpression of human alpha-synuclein. The mice were kept at a diet that consisted of the wheat grain of near isogenic lines differing in anthocyanin content for five-six months. The anthocyanin-rich diet was safe and possessed positive effects on cognitive function. Anthocyanins prevented deficits in working memory induced by Aß or a long-term grain mono-diet; they partially reversed episodic memory alterations. Both types of grain diets prolonged memory extinction and rescued its facilitation in the PD model. The dynamics of the extinction in the group fed with the anthocyanin-rich wheat was closer to that in a group of wild-type mice given standard chow. The anthocyanin-rich diet reduced alpha-synuclein accumulation and modulated microglial response in the brain of the transgenic mice including the elevated expression of arginase1 that marks M2 microglia. Thus, anthocyanin-rich wheat is suggested as a promising source of functional nutrition at the early stages of neurodegenerative disorders.

Effects of Grape Polyphenols on the Life Span and Neuroinflammatory Alterations Related to Neurodegenerative Parkinson Disease-Like Disturbances in Mice.

Functional nutrition is a valuable supplementation to dietary therapy. Functional foods are enriched with biologically active substances. Plant polyphenols attract particular attention due to multiple beneficial properties attributed to their high antioxidant and other biological activities. We assessed the effect of grape polyphenols on the life span of C57BL/6 mice and on behavioral and neuroinflammatory alterations in a transgenic mouse model of Parkinson disease (PD) with overexpression of the A53T-mutant human α-synuclein. C57BL/6 mice were given a dietary supplement containing grape polyphenol concentrate (GPC-1.5 mL/kg/day) with drinking water from the age of 6-8 weeks for life. Transgenic PD mice received GPC beginning at the age of 10 weeks for four months. GPC significantly influenced the cumulative proportion of surviving and substantially augmented the average life span in mice. In the transgenic PD model, the grape polyphenol (GP) diet enhanced memory reconsolidation and diminished memory extinction in a passive avoidance test. Behavioral effects of GP treatment were accompanied by a decrease in α-synuclein accumulation in the frontal cortex and a reduction in the expression of neuroinflammatory markers (IBA1 and CD54) in the frontal cortex and hippocampus. Thus, a GP-rich diet is recommended as promising functional nutrition for aging people and patients with neurodegenerative disorders.

Sham surgical embryo transfer affects offspring neurodevelopment and manifestation of hypertensive phenotype in ISIAH rats.

The study investigates how surgery during pregnancy, i.e., sham operation associated with embryo transfer, affects hypertensive phenotype in ISIAH rats genetically predisposed to hypertension. ISIAH rats born after maternal surgery at fourth day of pregnancy were compared with naturally conceived controls. Surgery during pregnancy in ISIAH rats caused acceleration of neurodevelopment in young offspring, as well as aggravating hypertension, suppressing exploratory activity, reducing hippocampal BDNF expression, and compensatory increasing of hippocampal neuronal density in adult ISIAH offspring. Maternal surgery during early pregnancy caused alterations in offspring phenotype in hypertensive ISIAH rat model.