Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension

The incidence rate and mortality of hypertension increase every year. Hypothalamic paraventricular nucleus (PVN) plays a critical role on the pathophysiology of hypertension. It has been demonstrated that the imbalance of neurotransmitters including norepinephrine (NE), glutamate (Glu) and γ-aminobutyric acid (GABA) are closely related to sympathetic overactivity and pathogenesis of hypertension. N-methyl-D-aspartate receptor (NMDAR), consisting of GluN1 and GluN2 subunits, is considered to be a glutamate-gated ion channel, which binds to Glu, and activates neuronal activity. Studies have found that the synthesis of respiratory chain enzyme complex was affected and mitochondrial function was impaired in spontaneously hypertensive rats (SHR), further indicating that mitochondria is associated with hypertension. Nuclear respiratory factor 1 (Nrf1) is a transcription factor that modulates mitochondrial respiratory chain and is related to GluN1, GluN2A, and GluN2B promoters. However, the brain mechanisms underlying PVN Nrf1 modulating sympathoexcitation and blood pressure during the development of hypertension remains unclear. In this study, an adeno-associated virus (AAV) vector carrying the shRNA targeting rat Nrf1 gene (shNrf1) was injected into bilateral PVN of male rats underwent two kidneys and one clip to explore the role of Nrf1 in mediating the development of hypertension and sympathoexcitation. Administration of shNrf1 knocked down the expression of Nrf1 and reduced the expression of excitatory neurotransmitters, increased the expression of inhibitory neurotransmitters, and reduced the production of reactive oxygen species (ROS), and attenuated sympathoexcitation and hypertension. The results indicate that knocking down Nrf1 suppresses sympathoexcitation in hypertension by reducing PVN transcription of NMDAR subunits (GluN1, GluN2A, and GluN2B), rebalancing PVN excitatory and inhibitory neurotransmitters, inhibiting PVN neuronal activity and oxidative stress, and attenuating sympathetic activity.

Potential therapeutic strategies of phytochemicals in neurodegenerative disorders

: Neurodegeneration is a syndrome that occurs through the loss of the neuronal system's structure and function. In the 21st century, major health issues are related to cognitive impairment and neurological disorders such as autism, learning disabilities, Huntington’s, cerebral palsy, schizophrenia, Alzheimer's, neuromuscular, lateral sclerosis, and Parkinson’s disease may be life-threatening. Various experimental and epidemiological studies reveal the risk factors associated with the disease, like oxidative stress, hypertension, antioxidant enzyme abnormalities, metabolic toxicity, advanced age, cytoskeletal abnormalities, genetic defects, autoimmunity, mineral deficiencies, and other vascular disorders. Various compounds have been screened for the treatment of neurodegenerative diseases (NDs), but, due to their side effects, they have solitary symptomatic benefits. Phytochemicals play a crucial role in maintaining the chemical balance of the brain by affecting the receptor function of specific inhibitory neurotransmitters. This review highlights the importance of phytochemicals for neurodegenerative diseases, in particular the possible mechanism of action of these natural compounds used for the treatment.

Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

Tetanus neurotoxin (TeNT) is a protein exotoxin produced by Clostridium tetani that causes the deadly spastic neuroparalysis of tetanus. It consists of a metalloprotease light chain and of a heavy chain linked via a disulphide bond. TeNT binds to the neuromuscular junction (NMJ) and it is retro-axonally transported into vesicular compartments to the spinal cord, where it is released and taken up by inhibitory interneuron. Therein, the catalytic subunit is translocated into the cytoplasm where it cleaves its target protein VAMP-1/2 with consequent blockage of the release of inhibitory neurotransmitters. Vaccination with formaldehyde inactivated TeNT prevents the disease, but tetanus is still present in countries where vaccination coverage is partial. Here, we show that small molecule inhibitors interfering with TeNT trafficking or with the reduction of the interchain disulphide bond block the activity of the toxin in neuronal cultures and attenuate tetanus symptoms in vivo. These findings are relevant for the development of therapeutics against tetanus based on the inhibition of toxin molecules that are being retro-transported to or are already within the spinal cord and are, thus, not accessible to anti-TeNT immunoglobulins.

An unusual cause for neck rigidity?

Otogenic tetanus is a subtype of cephalic tetanus, limited to the head & neck, but can progress to a more generalized form. Caused by the spore-forming bacillus, Clostridium tetani, It produces a potent toxin, tetanospasmin, preventing inhibitory neurotransmitters' release, hence causing rigidity.

Peptidergic modulation of fear responses by the Edinger-Westphal nucleus

Many neuronal populations that release fast-acting excitatory and inhibitory neurotransmitters in the brain also contain slower acting neuropeptides. These facultative peptidergic cell types are common, but it remains uncertain whether obligate peptidergic neurons exist. Our fluorescence in situ hybridization, genetically-targeted electron microscopy, and electrophysiological characterization data strongly suggest that neurons of the non-cholinergic, centrally-projecting Edinger-Westphal nucleus in mice are fundamentally obligately peptidergic. We further show, using fiber photometry, monosynaptic retrograde tracing, anterograde projection mapping, and a battery of behavioral assays, that this peptidergic population both promotes fear responses and analgesia and activates in response to loss of motor control and pain. Together, these findings elucidate an integrative, ethologically relevant function for the Edinger-Westphal nucleus and functionally align the nucleus with the periaqueductal gray, where it resides. This work advances our understanding of the peptidergic modulation of fear and provides a framework for future investigations of putative obligate peptidergic systems.

No balance between glutamate+glutamine and GABA+ in visual and motor cortices of the human brain

ABSTRACTTheoretical work, supported by electrophysiological evidence, asserts that a balance between excitation and inhibition (E/I) is critical for healthy brain function. In magnetic resonance spectroscopy (MRS) studies, the ratio of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters is often used as a proxy for this E/I balance. Recent MRS work found a positive correlation between GABA+ and Glx (glutamate+glutamine) in medial parietal cortex, providing validation for this proxy and supporting the link between the E/I balance observed in electrophysiology and that detected with MRS. Here we assess the same relationship, between GABA+ and Glx, in primary visual and motor cortices of resting male and female human participants. We find moderate to strong evidence that there is no positive correlation between these neurotransmitters in either location. We show this holds true when controlling for a range of other factors (i.e., demographics, signal quality, tissue composition, other neurochemicals) and regardless of the state of neural activity (i.e., resting/active). These results show that there is no brain-wide balance between excitatory and inhibitory neurotransmitters and indicates a dissociation between the E/I balance observed in electrophysiological work and the ratio of MRS-detected neurotransmitters.

Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance—as is the case in some neurological disorders/diseases (e.g. traumatic brain injury Alzheimer’s disease, stroke, epilepsy and substance abuse) and disorders of development (e.g. schizophrenia, Rhett syndrome and autism spectrum disorder)—leads to dysfunctional signaling, which can result in impaired cognitive and motor function, if not frank neuronal injury. At the cellular level, transmission of glutamate and GABA, the principle excitatory and inhibitory neurotransmitters in the central nervous system control excitatory/inhibitory balance. Herein, we review the synthesis, release, and signaling of GABA and glutamate followed by a focused discussion on the importance of their transport systems to the maintenance of excitatory/inhibitory balance.

MAHA PANCHAGAVYA GHRITA IN APASMARA (EPILEPSY) – A KETOSIS PERSPECTIVE

Epileptic seizures are caused due to imbalance in the excitatory and inhibitory neurotransmitters. Serum electrolytes like sodium, potassium and calcium play a key role in maintaining the epileptic threshold. In the quest of effective treatment in epilepsy ketogenic diet has been promising. It is found to increase the inhibitory Gamma amino butyric acid and thus increase the epileptic threshold. In this context Maha Panvhagavya Ghrita recommended in the treatment of Apasmara seems to be the drug of choice.

Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not from Cav2.3-deficient mice

Background: So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation (using kainic acid, KA) on the neural retina from wildtype and Cav2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed.Methods: Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient mice.Results: In mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study.Conclusion: Cu2+-dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.