Neuropharmacology & Neurotherapeutics

Mutual activation of microglia and astrocytes and the release of inflammatory factors, such as tumor necrosis factor alpha (TNF-a) and interleukin 1 beta (IL-1b). The release of inflammatory factors promotes the expression of the GluN1 and GluN2 subunits of the N-methyl-D-aspartic acid receptors (NMDAR) in postsynaptic neurons, allowing the binding of excitatory neuronal glutamate (Glu) and NMDAR released from presynaptic neurons and the inward flow of calcium ions (Ca²⁺) to act on neuronal synaptic plasticity by regulating the long-term potentiation (LTP) and MAPK/ERK phosphorylation pathways (also known as the Ras-Raf-MEK-ERK pathway, a chain of proteins in the cell that communicates a signal from a cell surface receptor to the DNA in the nucleus of the cell) through calmodulin-dependent kinase II (CaMKII). The release of inflammatory factors, on the other hand, directly promotes the development of neuroinflammation in the brain, secondary to the death of dopaminergic neurons, which leads to the development of Parkinson disease and the development of levodopa-induced dyskinesia (LID) in patients with Parkinson disease after years of L-DOPA administration by exacerbating the inflammatory response in the brain tissue and, thus, creating a vicious circle. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Both microglia and astrocytes have differentiated pro-inflammatory phenotypes that are neurotoxic and injurious to dopaminergic neurons, whereas the neuroprotective phenotypes are neuroprotective and protective of dopaminergic neurons. Under certain specific circumstances, the pro-inflammatory and anti-inflammatory phenotypes of microglia can be switched. Pro-inflammatory microglia secrete interleukin-1 alpha (IL-1a), interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and complement component 1q (C1q), which can convert astrocytes to a pro-inflammatory phenotype. Pro-inflammatory astrocytes secrete IL-1b, TNF-a, granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokine C-C motif ligand 2 (CCL2), which in turn activate pro-inflammatory microglia. The phenotypic transition of astrocytes remains to be clarified. Dashed lines with question marks indicate possible relationships, but evidence of a direct association is lacking. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Astrocyte-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of Parkinson disease. On exposure to inflammatory stimuli, astrocytes become activated A1 phenotype. A1 phenotype astrocytes secrete pro-inflammatory factors, such as interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and other inflammatory factors, which further induce neuroinflammation and neurotoxicity mechanisms in the human brain, damaging dopaminergic neurons. A1 phenotype astrocytes secrete pro-inflammatory factors, such as IL-1b, TNF-a, and other inflammatory factors. On the other hand, the neuroprotective mechanism of activated A2 phenotype astrocytes against Parkinson disease includes the release of anti-inflammatory cytokines into the brain as well as the upregulation of neuroprotective trophic factors, anti-inflammatory cytokines including transforming growth factor beta (TGF-β), which inhibit persistent neuroinflammation and, thus, protect dopaminergic neurons. Disease occurs when this balance in the organism is disrupted. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Microglia-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of Parkinson disease. Microglia turns into an activated M1 phenotype when exposed to stimuli, such as infection, trauma, and intoxication. M1 phenotype microglia secrete pro-inflammatory factors, which further induce neuroinflammatory and neurotoxic mechanisms in the human brain through processes such as enhanced phagocytic activity and increased interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and reactive oxygen species (ROS) generation, damaging dopaminergic neurons. On the other hand, the presence and stimulation of anti-inflammatory factors can lead to an activated M2 phenotype. The neuroprotective mechanism of M2 microglia against Parkinson disease involves the release of anti-inflammatory cytokines into the brain and the upregulation of neuroprotective trophic factors. The anti-inflammatory cytokines include interleukin 4 (IL-4), interleukin 10 (IL-10), and so on, which inhibit persistent neuroinflammation and consequently protect the dopaminergic neurons. Disease occurs when this balance in the organism is disrupted. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Systemic administration (intravenous) targets the central and the peripheral nervous system and is the only effective route to target the large and anatomically complex muscle tissue effectively. Intrathecal administration allows targeting of the brain, spinal cord, and peripheral nerves, whereas administration through unique anatomical locations, including directly to the brain parenchyma, facilitates specific targeting of the CNS. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

Cell transduction with a transgene of interest or a gene editing machinery can be achieved through viral or nonviral vectors, in vivo or ex vivo. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

The figure illustrates the main approaches for DNA- and RNA-directed therapies. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

The context around treatment modulates several biochemical pathways across different diseases and systems, and these pathways are the same as those modulated by drugs. The involvement of serotonin [5-hydroxytryptamine, 5-HT] receptors in hormonal responses and depression is not definitive. CCK, cholecystokinin; IL-2, interleukin-2; IFNγ, interferon- γ; COX, cyclooxygenase; NSAID, non-steroid anti-inflammatory drugs. (Contributed by Dr. Aziz Shaibani.)

(Illustration by Lyonsam/Dmitry Dzhus August 23, 2007. Public domain.)

(Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/deed.en.)

A 46-year-old man shows right-side postural tremors causing problems in writing. Patient had been taking sodium valproate for 4 years following two episodes of seizures. Tremors are present on right side, simulating parkinsonism. He did not have akinesia and rigidity. (Contributed by Dr. Ravindra Kumar Garg.)

Polish-American virologist Albert Sabin (1906-1993) developed the first effective trivalent live-attenuated (oral) poliovirus vaccine. (Contributed by Dr. Douglas Lanska. Source: Woodward T. The Armed Forces Epidemiological Board: its first fifty years. Falls Church, VA: Office of the Surgeon General, Department of the Army, 1990. Public domain photograph of a U.S. Army soldier taken in the course of the person’s official duties.)