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The basal ganglia: an overview
Published in Hans O Lüders, Deep Brain Stimulation and Epilepsy, 2020
This brief overview of the basal ganglia discussed the current model of basal ganglia with respect to its anatomical organization, neuro-chemistry, pharmacology and physiology. Much of the information presented in this overview is based on experiments in animal models of Parkinson’s disease and clinical studies in patients with movement disorders. Recent experiments suggest that the substantia nigra pars reticulata (SNr) may be important in modulating basal ganglia function. The SNr has also been postulated as a important player in the pathophysiology of epilepsy. A better understanding of SNr and its connections to the rest of the brain may allow us to understand the possible biological basis for the usefulness of deep brain stimulation (DBS) in epilepsy and other neuropsychiatric disorders. Recent investigations suggest that dopamine secreted locally into the SNr via the soma and dentrites of the substantia nigra pars compacta (SNc) neurons may play a significant role in modulating SNr activity.
Diet and exercise interventions to promote metabolic homeostasis in TBI pathology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Given that most of our current genome remains unchanged from the times of our ancestors,228 who had to perform abundant exercise for survival, the prevalence of inactivity in U.S. society is abnormal. The lack of physical activity and unhealthy eating are major factors for the prevalence of obesity in modern industrialized societies229,230 and derived metabolic dysfunctions, such as type 2 diabetes.229,231,232 A sedentary lifestyle or the lack of physical activity seems to be the primary causal factor responsible for about one third of deaths due to coronary heart disease, colon, cancer, and type 2 diabetes.233 Exercise enhances learning and memory under a variety of conditions (see Gomez-Pinilla and Hillman for review234) such that, in humans, it can attenuate the mental decline associated with aging235 and enhance the mental capacity of juveniles.236 Exercise, similar to diet, activates multiple hippocampal proteins associated with energy metabolism and synaptic plasticity,237 such as BDNF238,239 and insulin-like growth factor-1 (IGF-1). Blocking the action of BDNF during voluntary exercise decreases the effects of exercise on energy metabolic molecules, such as adenosine monophosphate-activated protein kinase (AMPK), suggesting that cellular energy metabolism interacts with BDNF-mediated plasticity.239 Exercise has the capacity to enhance learning and memory240–242 under a variety of conditions, from counteracting the mental decline that comes with age10 to facilitating functional recovery after brain injury and disease.11,243,244 Much like a healthy diet, physical activity is thought to benefit neuronal function. Exercise has been found to play an important role in the regulation of neurite development245 maintenance of the synaptic structure,246 axonal elongation,34 neurogenesis in the adult brain,242 and after brain and spinal cord injuries. Exercise has been shown to benefit in animal models of Parkinson’s disease.247 Exercise has also been shown to facilitate functional recovery. When physical therapy was implemented to treat Parkinson’s disease, patients showed signs of increased motor ability.248 Exercise applied after experimental TBI has also been shown to have beneficial effects, but these effects seem to depend on the postinjury resting period and the severity of the injury.249
New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Anna Stankiewicz, Katarzyna Kaczorowska, Ryszard Bugno, Aneta Kozioł, Maria H. Paluchowska, Grzegorz Burnat, Barbara Chruścicka, Paulina Chorobik, Piotr Brański, Joanna M. Wierońska, Beata Duszyńska, Andrzej Pilc, Andrzej J. Bojarski
The first ligands identified as PAMs for mGlu4 receptor, MPEP (1) and SIB-1893 (2)34,37 (Figure 1), were weak and not selective, as they showed cross-reactivity with mGlu5 receptor and mGlu1 receptor. Similarly, the ligand (–)-PHCCC (3, mGlu4 EC50 = 1.4 µM), originally thought to be a breakthrough, proved to be non-selective20, showing partial antagonist activity towards mGlu1 receptor as well as agonist activity towards mGlu634. However, further pharmacological studies with the use of (–)–PHCCC (3) revealed its efficacy in animal models of Parkinson’s disease7,20,33,35,38–44, depression45,46, anxiety47,48, epilepsy49,50, neuroprotection51 and oncology52 but also showed a poor pharmacokinetic profile, limited brain exposure and low aqueous solubility2,53,54.
Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds
Published in Xenobiotica, 2021
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun, Kevin J.H Allen, Madeline N. Owens, Jeremy S. Lee, Christopher P. Phenix, Ed S. Krol
Phase 1 metabolic studies utilizing hepatic microsomes in vitro are a typical first step in understanding drug metabolism. An advantage of using microsomes as an in vitro drug metabolism model is the ability to focus on generating sufficient amounts of presumptive P450-mediated phase I metabolites without contribution from other competing systems such as phase II metabolism and transporter-mediated processes (Temporal et al. 2017). It is our goal to use hepatic microsomes to determine whether our bifunctional compounds undergo Phase 1 metabolism and to identify those metabolic products. Several animal models of Parkinson’s disease exist so we have decided to carry out our assessment of in vitro metabolism using liver microsomes from several animals (mouse and rat) as well as human liver microsomes. An additional benefit to determining the metabolic stability of our bifunctional compounds is that knowledge of the regiochemistry of metabolic reactions can potentially inform less metabolically labile positions for incorporation of fluorine in our PET probe bifunctional analogues.
The molecular basis of platelet biogenesis, activation, aggregation and implications in neurological disorders
Published in International Journal of Neuroscience, 2020
Abhilash Ludhiadch, Abhishek Muralidharan, Renuka Balyan, Anjana Munshi
Parkinson’s disease (PD) is the most common neurodegenerative disease after Alzheimer’s disease (AD). Possible mechanisms are associated with genetic, environmental factors, mitochondrial dysfunction, oxidative stress, vascular risk factors and apoptosis. The results from various animal models of Parkinson’s disease indicate that neuroinflammation is a major contributor to the pathogenesis of disease [96]. The relationship between the severity of disease and MPV suggested that the inflammation theory might play a more important role in the later stages of the disease. Studies found that the platelet parameters like MPV are found to be higher in PD as compared to control groups [97,98]. There is a growing body of evidence showing that MPV can be used as a marker of disease progression for the low-grade inflammatory diseases and the efficacy of anti-inflammatory treatment for the inflammatory diseases [99,100]. The augmentation of MPV levels can be seen as a gage of the inflammatory process at Parkinson’s disease pathogenesis and in the future, MPV may be useful for determining the progression of the PD [98].