Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation

Arbo, Bruno Dutra; Schimith, Lúcia Emanueli; Santos, Michele Goulart dos; Hort, Mariana Appel

doi:10.1016/j.ejphar.2022.174800

Cited by 19 publications

(17 citation statements)

References 468 publications

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“…An example is chronic neuroinflammation triggered by post-traumatic brain injury that increases likelihood of mood disorders and early-onset dementias 34 . Given chronic administration necessary to treat chronic neuroinflammation, significant side effects and/or diminishing efficacy are common with current therapies 35 . Profound anti-neuroinflammatory effects we and others have observed using CBD, combined with evidence of a favorable side-effect profile 36 suggests it may improve ability to manage this difficult condition.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol inhibits neuroinflammatory responses and circuit-associated synaptic loss following damage to a songbird vocal pre-motor cortical-like region

Tripson

Litwa

Soderstrom

2023

Sci Rep

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The non-euphorigenic phytocannabinoid cannabidiol (CBD) has been used successfully to treat childhood-onset epilepsies. These conditions are associated with developmental delays that often include vocal learning. Zebra finch song, like language, is a complex behavior learned during a sensitive period of development. Song quality is maintained through continuous sensorimotor refinement involving circuits that control learning and production. Within the vocal motor circuit, HVC is a cortical-like region that when partially lesioned temporarily disrupts song structure. We previously found CBD (10 mg/kg/day) improves post-lesion vocal recovery. The present studies were done to begin to understand mechanisms possibly responsible for CBD vocal protection. We found CBD markedly reduced expression of inflammatory mediators and oxidative stress markers. These effects were associated with regionally-reduced expression of the microglial marker TMEM119. As microglia are key regulators of synaptic reorganization, we measured synapse densities, finding significant lesion-induced circuit-wide decreases that were largely reversed by CBD. Synaptic protection was accompanied by NRF2 activation and BDNF/ARC/ARG3.1/MSK1 expression implicating mechanisms important to song circuit node mitigation of oxidative stress and promotion of synaptic homeostasis. Our findings demonstrate that CBD promotes an array of neuroprotective processes consistent with modulation of multiple cell signaling systems, and suggest these mechanisms are important to post-lesion recovery of a complex learned behavior.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol inhibits neuroinflammatory responses and circuit-associated synaptic loss following damage to a songbird vocal pre-motor cortical-like region

Tripson

Litwa

Soderstrom

2023

Sci Rep

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“…An example is chronic neuroin ammation triggered by post-traumatic brain injury that increases likelihood of mood disorders and early-onset dementias 33 . Given chronic administration necessary to treat chronic neuroin ammation, signi cant side effects and/or diminishing e cacy are common with current therapies 34 . Profound anti-neuroin ammatory effects that we and others have observed using CBD, combined with evidence of a favorable side-effect pro le 35 suggests it may improve ability to manage this di cult condition.…”

Section: Cbd Anti-neuroin Ammatory Activitymentioning

confidence: 99%

Cannabidiol Inhibits Neuroinflammatory Responses and Circuit-Associated Synaptic Loss Following Damage to a Songbird Vocal Pre-motor Cortical-Like Region

Tripson

Litwa

Soderstrom

2023

Preprint

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The non-euphorigenic phytocannabinoid cannabidiol (CBD) has been used successfully to treat childhood-onset epilepsies. These conditions are associated with developmental delays that often include vocal learning. Zebra finch song, like language, is a complex behavior learned during a sensitive period of development. Song quality is maintained through continuous sensorimotor refinement involving circuits that control learning and production. Within the vocal motor circuit, HVC is a cortical-like region that when partially lesioned temporarily disrupts song structure. We previously found CBD (10 mg/kg/day) improves post-lesion vocal recovery. The present studies were done to understand mechanisms underlying CBD vocal protection. We found CBD-improved vocal recovery is accompanied by reduced expression of inflammatory mediators and oxidative stress markers. These effects were associated with regionally-reduced expression of the microglia marker TMEM119. As microglia are key regulators of synaptic reorganization, we measured synapse densities, finding significant lesion-induced circuit-wide decreases that were largely reversed by CBD. Synaptic protection was accompanied by NRF2 activation and BDNF/ARC/ARG3.1/MSK1 expression implicating mechanisms important to song circuit node mitigation of oxidative stress and promotion of synaptic homeostasis. Our findings indicate CBD improves post-lesion recovery of a complex learned behavior through an array of neuroprotective processes consistent with modulation of multiple cell signaling systems.

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“…Фармакологическая коррекция старческого нейровоспаления и сопряженных нейрокогнитивных нарушений, направленная на купирование провоспалительного состояния микроглии в стареющем мозге, включает нестероидные противовоспалительные препараты (НПВП) и синтетические аналоги глюкокортикоидов. Однако попытки корректировать цитотоксическое состояние стареющей микроглии с помощью широко применяемых НПВП оказались малоэффективными [33,37,66]. НПВП, действующие как неспецифические ингибиторы циклооксигеназы (ЦОГ), такие как индометацин, ацетилсалициловая кислота, мелоксикам, ибупрофен, могут снижать риск нейродегенеративных заболеваний лишь при условии применения на предсимптомных этапах болезни Альцгеймера (БА), а в симптоматической фазе неэффективны [66,67].…”

Section: фармакологическая модуляция цитотоксического состояния микро...unclassified

“…Однако попытки корректировать цитотоксическое состояние стареющей микроглии с помощью широко применяемых НПВП оказались малоэффективными [33,37,66]. НПВП, действующие как неспецифические ингибиторы циклооксигеназы (ЦОГ), такие как индометацин, ацетилсалициловая кислота, мелоксикам, ибупрофен, могут снижать риск нейродегенеративных заболеваний лишь при условии применения на предсимптомных этапах болезни Альцгеймера (БА), а в симптоматической фазе неэффективны [66,67].…”

Section: фармакологическая модуляция цитотоксического состояния микро...unclassified

Analysis of the causes and approaches to the regulation of the cytotoxic state of microglia in the aging brain

Терехина,

Кирова

2023

Zhurnal «Patologicheskaia Fiziologiia I Eksperimental`naia Terapiia»

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С момента эпохального открытия микроглии Пио дель Рио Ортегой минуло столетие многоплановых исследований, которые подтвердили гениально предсказанные испанским гистологом свойства и функции микроглиальных клеток. Однако причины возрастзависимого снижения гомеостатического/репаративного потенциала микроглии, также как подходы к модуляции цитотоксического состояния микроглии стареющего мозга остаются нерешенными вопросами на текущем этапе развития нейробиологии, в то время как возраст-ассоциированные нейровоспаление, нейродегенерация и нейродисфункция представляют собой угрожающий вызов современному «стареющему» социуму. Цель обзора – анализ представлений о причинах развития дистрофического/старческого фенотипа микроглии и подходов к увеличению ее нейрорепаративного потенциала в стареющем мозге. В работе обсуждаются прогрессирующая с возрастом глюкокортикоидная гиперпродукция и недостаточность проразрешающих/про-анаболических факторов как ведущие механизмы в развитии возрастных дистрофических изменений микроглии. Since the epoch-making discovery of microglia by Pio del Rio Ortega, a century of multifaceted studies has passed, which confirmed the properties and functions of microglial cells ingeniously predicted by the Spanish histologist. However, the reasons for the steady age-dependent decrease in the homeostatic/reparative potential of microglia, as well as approaches to modulating the cytotoxic state of microglia in the aging brain, remain unresolved issues at the current state of neurobiology, while age-associated neuroinflammation, neurodegeneration and neurodysfunction represent a threatening challenge to the modern “aging” society. The aim of this review was to analyze the ideas about the causes for the development of the microglia dystrophic/senescent phenotype of microglia and approaches to enhancing its neuroreparative potential in the aging brain. The authors discussed the age-related progression of glucocorticoid hyperproduction and the shortage of pro-resolving/pro-anabolic factors as the leading mechanisms in the development of age-related dystrophic changes in microglia.

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Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation

Cited by 19 publications

References 468 publications

Cannabidiol inhibits neuroinflammatory responses and circuit-associated synaptic loss following damage to a songbird vocal pre-motor cortical-like region

Cannabidiol inhibits neuroinflammatory responses and circuit-associated synaptic loss following damage to a songbird vocal pre-motor cortical-like region

Cannabidiol Inhibits Neuroinflammatory Responses and Circuit-Associated Synaptic Loss Following Damage to a Songbird Vocal Pre-motor Cortical-Like Region

Analysis of the causes and approaches to the regulation of the cytotoxic state of microglia in the aging brain

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