Brain Nerve Growth Factor Research Articles

Intranasal Insulin Eases Autism in Rats via GDF-15 and Anti-Inflammatory Pathways.

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally.

Abstract TP30: Exercise Postconditioning After Ischemic Stroke: Neuroprotection Through NGF/TRPV1-Mediated Astrocyte-Neuron Interaction

Introduction: Astrocytes activation and interaction with neurons potentially affect stroke outcomes. Transient receptor potential vanilloid 1 (TRPV1) participated in reducing brain injury and nerve growth factor (NGF) affected TRPV1 activation. The present study investigated neuroprotection induced by exercise postconditioning (PostE) and elucidated the mechanistic regulation of astrocytes-neuron crosstalk via NGF/TRPV1 pathway. Methods: Adult Sprague-Dawley rats received 2 h middle cerebral artery (MCA) occlusion, followed by 24 h of reperfusion. The treadmill exercise was then initiated 24 h after reperfusion for 3 days (PostE). Brain damage was determined by infarct volume, edema and apoptotic proteins expression (Bcl-2, BAX and Caspase-3). Neuroplasticity was determined by dendritic spine staining and protein expression of BDNF, GAP-43, PSD-95 and synaptophysin. Neuronal TRPV1 expression, astrocyte proliferation and astrocytic NGF expression was assessed with immunofluorescence. Primary astrocyte-neuron Transwell cultivation were used to determine the secretion of astrocytic NGF activating neural TRPV1. Interaction between TRPV1 and NGF or TRPV1 and A-kinase anchoring protein150 (AKAP150) were detected by immunofluorescence and Co-IP. Results: PostE significantly decreased brain damage and induced neuroplasticity in ischemic rats. PostE induced astrocyte proliferation and astrocytic NGF secretion, which, in turn, activated TRPV1 expression in neuron. Either NGF or TRPV1 inhibitor eliminated the neuroplasticity, while NGF inhibitor decreased TRPV1 expression, suggesting the potential regulating role of astrocytic NGF on TRPV1. Primary cells cultivation demonstrated a NGF/TRPV1 and TRPV1/AKAP150 interplays showing astrocyte-neuron communication. Conclusion: PostE induced neuroprotection, which was mediated by the activation of astrocytes and their interaction with neurons through the NGF/TRPV1 pathway, highlighting the significance of astrocyte-neuron crosstalk in post-stroke recovery processes.

Combined Effect of Decellularized Rat Brain Tissue and Nerve Growth Factor on 5 Neural Differentiation of PC12 Cell Line in 2D Cell Culture

Combined Effect of Decellularized Rat Brain Tissue and Nerve Growth Factor on 5 Neural Differentiation of PC12 Cell Line in 2D Cell Culture

Analgesic effects of Terminalia chebula extract are mediated by the suppression of the protein expression of nerve growth factor and nuclear factor-κB in the brain and oxidative markers following neuropathic pain in rats.

Due to the complications related to the use of the current pharmacological approach for the alleviation of neuropathic pain, searching for effective compound with fewer complications is a requirement of the present era. It is well known that the pathophysiological mechanism of neuropathic pain is related to excessive inflammation in the nervous system. Hence, the present study focuses on whether the potential analgesic effects of Terminalia chebula (TC) extract are mediated by the changes in the protein expression of nerve growth factor (NGF) and nuclear factor-kappa B (NF-κB) in the brain in a rat model of sciatic nerve chronic constriction injury (CCI). Neuropathic pain was induced by the left sciatic nerve CCI. Male Wistar rats were assigned to three groups: sham, CCI, and CCI + TC (40mg/kg). Animals received either normal saline (1 mL) or the aqueous-alcoholic extract of TC (40mg/kg) for 30 days via gavage needles once a day. Cold allodynia and anxiety-like behaviors were examined one day before CCI surgery (day - 1), as well as days 2, 7, 14, and 30 following CCI. We also assessed the effects of the TC extract oxidative stress markers on day 30 following CCI. Moreover, a western blot analysis was performed on day 30 following CCI to evaluate the effects of the TC extract on the protein expression of NGF and NF-κB in the brain. Oral gavage of the TC extract significantly decreased cold allodynia on days 2 and 14 following CCI. Additionally, the CCI model of chronic pain significantly increased the protein expression of NGF and NF-κB in the brain on day 30 following CCI. Furthermore, the TC extract significantly decreased the protein expression of NGF and NF-κB in the brain. The TC extract also significantly increased the brain glutathione (GSH) content and decreased the malondialdehyde (MDA) content. It is suggested that the analgesic effects of the TC extract are mediated by the suppression of brain NGF, NF-κB, and by its antioxidant activity in the brain following neuropathic pain in rats.

Transgenerational Abnormalities Induced by Paternal Preconceptual Alcohol Drinking: Findings from Humans and Animal Models.

Alcohol consumption during pregnancy and lactation is a widespread preventable cause of neurodevelopmental impairment in newborns. While the harmful effects of gestational alcohol use have been well documented, only recently, the role of paternal preconceptual alcohol consumption (PPAC) prior to copulating has drawn specific epigenetic considerations. Data from human and animal models have demonstrated that PPAC may affect sperm function, eliciting oxidative stress. In newborns, PPAC may induce changes in behavior, cognitive functions, and emotional responses. Furthermore, PPAC may elicit neurobiological disruptions, visuospatial impairments, hyperactivity disorders, motor skill disruptions, hearing loss, endocrine, and immune alterations, reduced physical growth, placental disruptions, and metabolic alterations. Neurobiological studies on PPAC have also disclosed changes in brain function and structure by disrupting the growth factors pathways. In particular, as shown in animal model studies, PPAC alters brain nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) synthesis and release. This review shows that the crucial topic of lifelong disabilities induced by PPAC and/or gestational alcohol drinking is quite challenging at the individual, societal, and familial levels. Since a nontoxic drinking behavior before pregnancy (for both men and women), during pregnancy, and lactation cannot be established, the only suggestion for couples planning pregnancies is to completely avoid the consumption of alcoholic beverages.

The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer's Cholinergic Atrophy.

The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer’s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer’s disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.

Stem cell-derived exosomes and copper sulfide nanoparticles attenuate the progression of neurodegenerative disorders induced by cadmium in rats

The goal of the current study was to investigate the therapeutic effects of exosomes derived from mesenchymal stem cells (MSCs-Exo) and copper sulfide nanoparticles (CuSNPs) as biomaterials in order to understand the mechanisms that contribute to overcoming cadmium (Cad) induced neurological disorders in rats. Animals were divided into five groups (n = 10): group 1 was served as a negative control and receive vehicle saline (Con), group 2 Positive control groups were received Cad as cadmium chloride at a dose of 20 mg/kg/day for six weeks (Cad group), group 3 was received Cad plus MSCs-Exo as a single dose of 100 μLi. v. (Cad + MSCs-Exo), group 4 was received Cad plus CuSNPs at a dose of 6.5 mg/kg orally (Cad + CuSNPs), group 5 was received Cad + MSCs-Exo + CuSNPs for six weeks. However, the activities of each acetylcholine (Ach), acetylcholinesterase (AchE), total antioxidant status (TAC) were measured. Also, the levels of ROS, nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), Brain brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were evaluated. Beneficial effects on the behavior of animals were observed after treatment with MSCs-Exo and CuSNPs. Furthermore, the administration of MSCs-Exo and CuSNPs have been improve the TAC, BDNF and NGF via ameliorating the oxidative stress and inflammatory markers. Moreover, Histopathological studies had shown that great development in the brain of Cad rats treated with MSCs-Exo and CuSNPs. In conclusion, this study offers an overview of innovative stem cell therapy techniques and how to integrate them with nanotechnology to boost therapeutic performance.

Carissa macrocarpa Leaves Polar Fraction Ameliorates Doxorubicin-Induced Neurotoxicity in Rats via Downregulating the Oxidative Stress and Inflammatory Markers.

Chemotherapeutic-related toxicity exacerbates the increasing death rate among cancer patients, necessitating greater efforts to find a speedy solution. An in vivo assessment of the protective effect of the C. macrocarpa leaves polar fraction of hydromethanolic extract against doxorubicin (Dox)-induced neurotoxicity was performed. Intriguingly, this fraction ameliorated Dox-induced cognitive dysfunction; reduced serum ROS and brain TNF-α levels, upregulated the brain nerve growth factor (NGF) levels, markedly reduced caspase-3 immunoexpression, and restored the histological architecture of the brain hippocampus. The in vivo study results were corroborated with a UPLC-ESI-MS/MS profiling that revealed the presence of a high percentage of the plant polyphenolics. Molecular modeling of several identified molecules in this fraction demonstrated a strong binding affinity of flavan-3-ol derivatives with TACE enzymes, in agreement with the experimental in vivo neuroprotective activity. In conclusion, the C. macrocarpa leaves polar fraction possesses neuroprotective activity that could have a promising role in ameliorating chemotherapeutic-induced side effects.

Involvement of Oxidative Stress and Nerve Growth Factor in Behavioral and Biochemical Deficits of Experimentally Induced Musculoskeletal Pain in Mice: Ameliorative Effects of Heraclin.

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and institutingmechanism-based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, alteredbrain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling. Graphical Abstract.

Nerve growth factor in the psychiatric brain.

The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.

Impacts of Sex and Exposure Duration on Gene Expression in Zebrafish Following Perfluorooctane Sulfonate Exposure.

Perfluorooctane sulfonate (PFOS) is a member of the anthropogenic class of perfluorinated alkyl acids (PFAAs) and one of the most frequently detected PFAAs in water, humans, mammals, and fish around the world. The zebrafish (Danio rerio) is a small freshwater fish considered an appropriate vertebrate model for investigating the toxicity of compounds. Previous investigations showed tissue-specific bioaccumulation and alterations in the expression of fatty acid-binding proteins (fabps) in male and female zebrafish, potentially due to interactions between PFAA and fatty acid transporters. In addition, a number of neurological impacts have been reported as a result of human and animal exposure to PFAAs. Therefore, the present comprehensive study was designed to investigate whether PFOS exposure affects the expression of genes associated with fatty acid metabolism (fabp1a, fabp2, and fabp10a) in zebrafish liver, intestine, heart, and ovary and genes involved in the nervous system (acetylcholinesterase, brain-derived neurotrophic factor, choline acetyltransferase, histone deacetylase 6, and nerve growth factor) in brain and muscle. The results indicate alterations in expression of genes associated with fatty acid metabolism and neural function that vary with both exposure concentration and sex. In addition, our findings highlight that expression of these genes differs according to exposure duration. The present results extend the knowledge base on PFOS effects to other tissues less often studied than the liver. The findings of the present investigation provide a basis for future studies on the potential risks of PFOS as one of the most abundant PFAAs in the environment. Environ Toxicol Chem 2020;39:437-449. © 2019 SETAC.

The low levels of nerve growth factor and its upstream regulatory kinases in prion infection is reversed by resveratrol

Resveratrol shows ability to eliminate prion replication, but the exact mechanism for prion eradication was not clear yet. Our previous studies demonstrate a downregulation of brain-derived nerve growth factor (BDNF) during prion infection, meanwhile recovery of cerebral nerve growth factor (NGF) level by resveratrol treatment has been reported in other neurodegenerative models. To obtain the possible changes of brain NGF and its upstream regulatory cascade during prion infection and after removal of prion propagation, the levels of NGF and its upstream regulatory factors in various prion-infected and prion-eradicated SMB cell lines and mice brains inoculated with various SMB cellular lysates were assessed with various methodologies. The levels of NGF were significantly decreased during prion replication, while recovered after removal of PrPSc by resveratrol in vitro. Morphological assays revealed that the NGF signals mainly colocalized within neurons, but not in the proliferative astrocytes and microglia. The upstream positive regulatory kinases, such as p-CREB, p-CaMKIV, CaMKK2 were decreased in the prion infected cells and mice brains, whereas the negative regulatory one, p-CaMKK2, was increased. The aberrant situations of those kinases in prion infected cell lines or mice brains could be also partially reversed by removal of prion agent. Moreover, we demonstrated that the signals of CaMKK2 and p-CaMKK2 were also distributed predominately in neurons in the brain tissues. The data illustrate a direct linkage of abnormally repressive NGF and its upstream regulatory kinases with prion infection. Resveratrol has not only the ability to inhibit prion replication, but also to improve the expression of NGF via CaMKK2/CaMKIV cascade, which might benefit the microenvironment in brains.

Acute stimulation of vagus nerve modulates brain neurotrophins, and stimulates neuronal plasticity in the hippocampus of adult male rats

The present study was aimed at evaluating whether single intermittent acute cervical vagus nerve stimulation (ACVS), pro-vided at a frequency which exhibits a clinical efficacy, may influence brain neurotrophins and hippocampal plasticity. With this purpose, the brain of adult male rats undergoing ACVS was used to analyze the expression of Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) in brain areas known to synthetize these growth factors, and the expression the neural cell adhesion molecule (NCAM), the synaptophysin (SYP) and biosynthetic GABA (GAD67) in the hippocampus. The effects of ACVS on NGF and BDNF protein and mRNA in hippocampus, hypothalamus and cortex two hours after stimulation were shown to be dependent on the frequencies of ACVS stimulation. Prolonged (three days post stimulation) modifications of NGF and BDNF were also observed in the hippocampus of ACVS rats. An early enhancement of the plasticity markers NCAM, SYP and GAD67 was also found in ACVS hippocampus. Three days after stimulation, NCAM and GAD67 levels were still higher than controls. Immunohistochemistry confirms the stimulatory effects of ACVS on GABA showing an increase in GAD67-positive cells in the dentate gyrus and CA3 hippocampal areas. This study shows that ACVS affects brain NGF and BDNF synthesis in a frequency-dependent manner. Neurotrophins changes are associated with increased hippocampal plasticity, as demonstrated by the observed molecular and morphological modifications. These findings support the role of brain neurotrophins in the ACVS mechanism of action.

Benefits of Gardening Activities for Cognitive Function According to Measurement of Brain Nerve Growth Factor Levels.

The objective of this study was to determine the effects of gardening activities in senior individuals on brain nerve growth factors related to cognitive function. Forty-one senior individuals (age 76.6 ± 6.0 years) were recruited from the local community in Gwangjin-gu, Seoul, South Korea. A 20-min low-to-moderate intensity gardening activity intervention, making a vegetable garden, was performed by the subjects in a garden plot located on the Konkuk University (Seoul, South Korea) campus. The gardening involved six activities including cleaning a garden plot, digging, fertilizing, raking, planting/transplanting, and watering. To determine the effects of the gardening activities on brain nerve growth factors related to memory, blood samples were drawn twice from each subject before and after the gardening activity by professional nurses. The levels of brain nerve growth factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), were analyzed. Levels of BDNF and PDGF were significantly increased after the gardening activity. This study revealed a potential benefit of gardening activities for cognitive function in senior individuals.

GM6 Attenuates Alzheimer's Disease Pathology in APP Mice.

Alzheimer's disease (AD) results in the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aβ peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.

Evaluation of the BDNF, NGF, NT3 and NT4 Genes Expressions in the Brains of Neonatal Mice with Hypothyroidism

Background and Aim: Thyroid is one of the endocrine glands, (T3 and T4) play a significant role in the development of prenatal brain and the following stages. The study aimed to evaluate the effect of hypothyroidism on the amount of expression of NT4, NT3, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in brain of one-day rat neonates with hypothyroidism.Materials and Methods: In total, 25 mature mice of Albino NMRI race were selected after mating, divided into three group, control, as well as low-dose and high-dose intervention groups. Samples of the control group received pure water during pregnancy, whereas subjects of the intervention group with low and high doses of the medication were administered with 20 mg and 100 mg methimazole powder (dissolved in 100 cc water), respectively. After child delivery, blood samples were obtained from mother mice to determine the level of T3 and T4 in blood serum. Following that, the brain of one-day mice were removed by surgery and assessed to determine the amount of expression of NT4, NT3, NGF and BDNF using the complete kit of RT-PCR.Results: Levels of T4 and T3 in the control group were 28 ug/dl and 1.59 ug/dl, respectively. In the low-dose intervention group, the amounts of the mentioned hormones were 8 ug/dl and 0.85 ug/dl, significantly, indicating a significant reduction in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group. Moreover, T4 and T3 were 6 ug/dl and 0.79 ug/dl in the high-dose group, respectively, conveying a significant decrease in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group (P&lt;0.05).

Maternal Cannabinoid Use Alters Cannabinoid (CB1) and Endothelin (ETB) Receptor Expression in the Brains of Dams but Not Their Offspring

According to the 2015 National Survey on Drug Use and Health, cannabis (marijuana) is the most commonly used recreational drug in the US. Among pregnant women aged 14-55 years, 3.4% were cannabis users. Presently, little is known about the neurodevelopmental effect of cannabis use during pregnancy and/or nursing on neonates. Endothelin (ET) is essential for normal development of the central nervous system (CNS). Decreases in ET_B receptor expression correlate with a decline in nerve growth factor (NGF) and an increase in vascular endothelial growth factor (VEGF) in postnatal brain. Activation of ET_B and cannabinoid 1 (CB₁) receptors each promote neurogenesis and enhance angiogenesis, indicating that both ET and CB systems play a critical role during early CNS development. Hence the purpose of this study was to determine whether maternal CB abuse during pregnancy and lactation alters the expression of ET_B receptors, CB₁ receptors, VEGF, and NGF in the postnatal rat brain. Sixteen pregnant Sprague-Dawley rats were administered either saline or anandamide (AEA) at a dose of 3 mg/kg/day i.p. from gestational day 7 and continued through weaning on postnatal day (PND) 21. Rat pups were subdivided into 4 subgroups and sacrificed on PND 2, 7, 14, and 28. Brain tissue of the pups and dams (sacrificed on PND 21) was analyzed via Western blot for the expression of ET_B receptors, CB₁ receptors, VEGF, and NGF. AEA-exposed dams had significantly fewer live births (p = 0.027), and their pups presented with significantly lower body weights on PND 7 (p = 0.013) and PND 28 (p = 0.018). There was no significant difference noted in ET_B receptor, CB₁ receptor, NGF, or VEGF expression in the pup brains. In all pups, brain ET_B receptor expression decreased and CB₁ receptor expression increased with age. In the AEA-exposed dam brain, however, there was a decrease in ET_B receptor (p = 0.043) and an increase in CB₁ receptor expression (p = 0.033). AEA exposure during pregnancy appears to affect fetal viability and postnatal weight gain in offspring while not altering the expression patterns of ET_B receptors, CB₁ receptors, NGF, or VEGF in the pup brain. The observed trend to an increase in CB₁ receptor expression concurrent with a decrease in ET_B receptor expression in both dams and pups may point to a homeostatic regulation between these 2 systems in CNS development and neuroprotection.

Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ-induced diabetic rats.

Diabetic encephalopathy is characterized by cognitive impairment and neuroinflammation, deficient neurotrophic support, and neuronal and synaptic loss. Ghrelin, a 28 amino acid peptide, is associated with neuromodulation and cognitive improvement, which has been considered as a potential protective agent for several neurodegenerative diseases. Here we sought to investigate the role of ghrelin in preventing diabetic-related neuropathology. We found that ghrelin attenuated astrocytic activation and reduced levels of interleukin-6 and tumor necrosis factor-α in streptozotocin-induced diabetic rats. In addition, ghrelin inhibited p38 mitogen-associated protein kinase activation. The upregulation of nerve growth factor (NGF) precursor and matrix metalloproteinase (MMP)-9 and downregulation of mature NGF and MMP-7 in the diabetic brain were reversed by ghrelin. Treatment with ghrelin elevated synaptophysin expression and synaptic density in diabetic rats. Taken together, our results demonstrate that ghrelin ameliorates diabetes-related neurodegeneration by preventing NGF dysmetabolism and synaptic degeneration through regulating MMP levels as well as inhibiting neuroinflammation.

The endocannabinoid system and NGF are involved in the mechanism of action of resveratrol: a multi-target nutraceutical with therapeutic potential in neuropsychiatric disorders.

Resveratrol is a polyphenolic compound with antioxidant, anti-inflammatory, and neuroprotective effects. It has also shown antidepressant-like effects in the behavioral studies; however, its mechanism(s) of action merit further evaluation. The interaction between the nerve growth factor (NGF) and endocannabinoid system (eCBs) and their contribution to the antidepressant or emotional activity prompted us to evaluate their implications in the mechanism of action of resveratrol. After single and 4-week intraperitoneal (i.p.) once-daily injections of resveratrol (40, 80, and 100 mg/kg), amitriptyline (2.5, 5, and 10 mg/kg), or clonazepam (10, 20, and 40 mg/kg) into male Wistar rats, eCB and NGF contents were quantified in the brain regions implicated in the modulation of emotions by isotope-dilution liquid chromatography/mass spectrometry and Bio-Rad protein assay, respectively. In the case of any significant alteration of brain eCB or NGF level, the effect of pre-treatment with cannabinoid CB1 or CB2 receptor antagonist (AM251 or SR144528) was investigated. Four-week treatment with resveratrol or amitriptyline resulted in a significant and sustained enhancement of NGF and eCB contents in dose-dependent and brain region-specific manner. Neither acute nor 4-week treatment with clonazepam affected brain eCB or NGF contents. Pre-treatment with AM251 (3 mg/kg), but not SR144528, prevented the enhancement of NGF protein levels. AM251 exhibited no effect by itself. Resveratrol like the classical antidepressant, amitriptyline, affects brain NGF and eCB signaling under the regulatory drive of CB1 receptors.

Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model

Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss.