Mechanistic Aspects of Neurodegeneration in Alzheimer’s Disease and the Role of Phytochemicals as Restorative Agents
Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu in Phytomedicine and Alzheimer’s Disease, 2020
Neurotransmitters, also known as endogenous chemical messengers, enable neurotransmission of signals across the chemical synapses. To maintain the homeostatic balance of neural circuits, diverse sets of inhibitory interneurons regulate the activity of excitatory neurons in the CNS. Impaired co-activation of excitatory and inhibitory neurons, such as substantial loss of gamma amino butyric acid (GABA)-ergic interneurons, dysfunction of interneurons due to loss of their afferent excitatory input, changes in their receptors, and an imbalance of the different neurotransmitters, like glutamate, acetylcholine, dopamine, and serotonin, have been proposed in many neurobiological disorders like AD. AD is a neurodegenerative disorder which is characterized by memory loss, and behavioral and psychological symptoms of dementia (Southwell et al., 2014). It is hypothesized that altered reuptake of neurotransmitters by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT), are involved in the neurotransmission imbalance in AD. Compared with control subjects, the protein and mRNA levels of VGLUTs, EAAT1–3, VAChT, and SERT are reduced significantly in AD subjects; playing a contributory role to the recognized cholinergic deficiency, alteration in glutamatergic recycling and reduced SERT levels could exacerbate depressive symptoms in AD (Isaacson and Scanziani, 2011).
Neurotransmitters and pharmacology
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
The preceding pages provide considerable detail concerning the process of neurotransmission in the nervous system. It is clear that neurotransmission is the fundamental basis of communication between neurons of the various brain areas. Virtually any of the players in neurotransmission are potential sites of modulation and neuroplasticity in the context of brain injury (and recovery). Additionally, neurotransmission is the principal target for drugs that affect the nervous system. Although it is impossible to provide a concise summary of the broad array of topics covered in this chapter, the editor felt that some type of summary of the clinically relevant drugs showing the neurotransmitters through which they exert their action would be useful for the busy practitioner, and we fully agree. Therefore, an appendix (see Appendix 16-A) has been provided at the end of this chapter to summarize these relationships and to give the reader a quick mechanism for linking the drugs to the neurotransmitters. It should be noted, however, that we have only included the drugs discussed in this chapter. Although they represent some of the more popular ones in use today, they are by no means the only ones available. Practitioners of rehabilitation as well as other specialties in medicine must be aware that pharmacology is a constantly changing field with new drugs being introduced every month. It is hoped that this chapter also provides a foundation that will allow the reader to appreciate and understand the mechanism of action of new (undiscovered) drugs that will be introduced in the future.
Insulin and Brain Reward Systems
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
It is worth mentioning that the dysfunction of the reward system mediated by dopamine is closely associated with substance use disorders and obesity (128, 129), while central dopaminergic neurotransmission in the NAcc, prefrontal cortex, and striatum is sensitive to metabolic and energy balance stages (130–133), as well as changes in insulin signaling (134). Continuous firing of the dopaminergic neuron causes the downregulation of the expression of the D1 dopamine receptor in the postsynaptic neuron, and the dopamine release in baseline conditions will also be downregulated to preserve homeostasis (120). Further, insulin binds directly to IRs expressed on dopamine neurons (135, 136) and regulates dopamine signaling, reward processing, and reward behavior by increasing dopamine transporter (DAT) density and function in the striatum (78, 137, 138). Insulin also interacts with D2-like dopamine receptors to affect dopamine-linked reward behaviors in humans and animals (139, 140), significantly modifies brain reward thresholds (141), and attenuates preference for food intake, and hedonic food intake under satiety (137, 142).
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
One promising candidate is the selective high affinity TSPO ligand XBD173 (AC-5216/emapunil) which exerts rapid anxiolytic effects in animal models and humans by elevating neurosteroids e.g. 3α,5α-THPROG [132]. XBD173 potentiated GABA-mediated synaptic transmission, which was prevented by finasteride [132]. These data provide further evidence that neurosteroidogenesis is involved in the differential effects of TSPO ligands on GABAergic neurotransmission. In contrast to the TSPO ligands RO5-4864 and PK95111, XBD173 has been clinically proven for efficacy, safety and tolerability also in humans. Thus, XBD173 might have a therapeutic potential for critical care medicine. The latter findings suggest that TSPO ligands have the potential to replace benzodiazepines in several clinical settings.
Datumetine exposure alters hippocampal neurotransmitters system in C57BL/6 mice
Published in Drug and Chemical Toxicology, 2022
Azeez Olakunle Ishola, Aminu Imam, Moyosore Salihu Ajao
Electron microscopy studies on the synapse revealed that datumetine exposed animals showed a reduction in the number of viable synapses with 1.0 mg/kg Datumetine animals showing the greatest reduction compared to controls. It is on record that overactivation of NMDAR leads to synaptic loss (Talantova et al.2013, Zhou et al.2013, Lewerenz and Maher 2015). This observation may be due to the persistent interaction of datumetine with NMDAR (Ishola et al.2020). The postsynaptic density was thicker in datumetine exposed animals with a great reduction in presynaptic vesicles. Chemical neurotransmission is through the release of synaptic vesicles (Trkanjec and Demarin 2001, Ikeda and Bekkers 2009) which are tightly regulated by re-uptake back to the presynaptic neurons (Piedras-Renteria et al.2004, Dickman et al.2012, Davis and Muller 2015). Datumetine greatly reducing the number of synaptic vesicles showed that either reuptake of the vesicles is altered, or rate of production is not balanced with the rate of release (Wang et al.2016, Li and Kavalali 2017). Another possible explanation may be that NMDAR binding with datumetine increases the affinity of presynaptic NMDAR for glutamate thereby increasing the release of neurotransmitters (Reimer et al.1998, Takamori 2016).
Towards a functional connectome in Drosophila
Published in Journal of Neurogenetics, 2020
Katrin Vogt
In all animals, receptors situated at the postsynaptic density are not only modulated by pre-synaptically released neurotransmitters, but also by molecules and peptides released extrasynaptically or from other nearby presynaptic sites (Bentley et al., 2016; De-Miguel & Trueta, 2005; Lendvai & Vizi, 2008). Serotonergic neuromodulation occurs by both synaptic communication as well as volume release (Fuxe & Borroto-Escuela, 2016). In the adult fly, serotonin has been shown to nonsynaptically modulate optic lobe neurons (Gschweng et al., 2019). Serotonergic neurons in vertebrates and invertebrates have widespread impacts across different brain areas and modulate many different cells, sometimes in opposing manners. The mechanisms of volume-released neurotransmission can also involve glial cells that contribute by taking up neurotransmitters (Henn & Hamberger, 1971). Though non-synaptic neuromodulation cannot be predicted by the connectome, it can significantly influence neural processing and therefore the functional circuits that give rise to behavior (Bargmann, 2012; Bargmann & Marder, 2013; Marder, 2012).
Related Knowledge Centers
- Axon Terminal
- Dendrite
- Gabaergic
- Glutamic Acid
- Neurotransmitter
- Cannabinoid
- Receptor
- Neuron
- Retrograde Signaling
- Calcium In Biology