Scholarlink

<p>BACKGROUND. Cannabinoid type 2 receptor (CB<sub>2</sub>) activation works against neurotoxic events that kill motor neurons in amyotrophic lateral sclerosis. Given that amyotrophic lateral sclerosis is a neuromuscular pathology with the skeletal muscle being also affected, we were interested in deciphering whether peripheral CB<sub>2</sub> may contribute in these beneficial effects. METHODS. To this end, we used two CB<sub>2</sub> agonists: (i) RO-6866945, which crosses the blood-brain barrier (BBB) and acts at both Central Nervous System (CNS) and peripheral compartments; and (ii) RO-6871304, which is a peripherally-restricted ligand that activates CB<sub>2</sub> outside the BBB. Both agonists have been evaluated in SOD-1 and TDP-43 transgenic male animals. RESULTS. In both cases, their i.p. administration improved the neurological status of these mice, preserved their spinal motor neurons and attenuated glial reactivity. They also recovered those muscle fibers denervated by the pathology in SOD-1 transgenic mice. To confirm that the efficacy of RO-6871304 is not derived from a possible BBB damage in amyotrophic lateral sclerosis mice that may allow this agonist to reach the CNS, we analyzed their concentrations in neural tissues after acute administration in both experimental models. Our data confirmed that RO-6866945 was detected in the brain, while RO-6871304 was not, whereas both compounds were found in the plasma. CONCLUSIONS. In summary, our data suggest that CB<sub>2</sub> located at peripheral sites (skeletal muscle, immune cells, others) may be responsible of therapeutic effects showed by compounds targeting these receptors in amyotrophic lateral sclerosis. Our study may be of critical importance to move CB<sub>2</sub> agonists in amyotrophic lateral sclerosis towards the clinical scenario.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Relevance of a peripheral site of action outside the brain-blood barrier for the beneficial effects of CB2 receptor activation in experimental ALS in male mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月10日

查看全文
  • Marta Gómez-Almería,
  • Claudia Gonzalo-Consuegra,
  • Carmen Rodríguez-Cueto,
  • María Cabañas-Cotillas,
  • Alberto Jiménez-Amor,
  • Isabel Machín-Díaz,
  • Matthias B. Wittwer,
  • Pawel Dzygiel,
  • Diego Clemente,
  • Uwe Grether,
  • Javier Fernández-Ruiz,
  • Eva de Lago

摘要

BACKGROUND. Cannabinoid type 2 receptor (CB2) activation works against neurotoxic events that kill motor neurons in amyotrophic lateral sclerosis. Given that amyotrophic lateral sclerosis is a neuromuscular pathology with the skeletal muscle being also affected, we were interested in deciphering whether peripheral CB2 may contribute in these beneficial effects. METHODS. To this end, we used two CB2 agonists: (i) RO-6866945, which crosses the blood-brain barrier (BBB) and acts at both Central Nervous System (CNS) and peripheral compartments; and (ii) RO-6871304, which is a peripherally-restricted ligand that activates CB2 outside the BBB. Both agonists have been evaluated in SOD-1 and TDP-43 transgenic male animals. RESULTS. In both cases, their i.p. administration improved the neurological status of these mice, preserved their spinal motor neurons and attenuated glial reactivity. They also recovered those muscle fibers denervated by the pathology in SOD-1 transgenic mice. To confirm that the efficacy of RO-6871304 is not derived from a possible BBB damage in amyotrophic lateral sclerosis mice that may allow this agonist to reach the CNS, we analyzed their concentrations in neural tissues after acute administration in both experimental models. Our data confirmed that RO-6866945 was detected in the brain, while RO-6871304 was not, whereas both compounds were found in the plasma. CONCLUSIONS. In summary, our data suggest that CB2 located at peripheral sites (skeletal muscle, immune cells, others) may be responsible of therapeutic effects showed by compounds targeting these receptors in amyotrophic lateral sclerosis. Our study may be of critical importance to move CB2 agonists in amyotrophic lateral sclerosis towards the clinical scenario.