morphinans and Neurodegenerative-Diseases

Sinomenine is one of the most widely known alkaloids owing to different therapeutic properties including anti-inflammatory and immunosuppressive activities, as well as the potency in neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Sinomenine has been studied as a potential anti-inflammatory agent through appropriate structural modifications. Recently, a number of such approaches have been attempted in various laboratories with great success. Several series of derivatives have been synthesized with changes at rings A, B, C and D. Herein, we present an up to date review of modifications and bioactivities of important modified derivatives. These studies offer interesting knowledge on the bioactivity and structural specificity of sinomenine, providing better understanding of the structure-activity relationships (SAR) between designing and development of sinomenine derivative with better therapeutic and lower side effects.

Topics: Animals; Anti-Inflammatory Agents; Humans; Immunosuppressive Agents; Morphinans; Neurodegenerative Diseases

Morphinans are a class of compounds containing the basic structure of morphine. It is well-known that morphinans possess diverse pharmacological effects on the central nervous system. This review will demonstrate novel neuroprotective effects of several morphinans such as, dextromethorphan, its analogs and naloxone on the models of multiple neurodegenerative disease by modulating glial activation associated with the production of a host of proinflammatory and neurotoxic factors, although dextromethorphan possesses neuropsychotoxic potentials. The neuroprotective effects and the therapeutic potential for the treatment of excitotoxic and inflammatory neurodegenerative diseases, and underlying mechanism of morphinans are discussed.

Topics: Animals; Astrocytes; Dextromethorphan; Humans; Morphinans; Naloxone; Neurodegenerative Diseases; Neuroglia; Neurons; Neuroprotective Agents

Neuro-inflammation plays a pivotal role in numerous neurodegenerative disorders, such as Parkinson's disease (PD). Traditional anti-inflammatory drugs have limited therapeutic use because of their narrow spectrum and severe side effects after long-term use. Morphinans are a class of compounds containing the basic morphine structure. The following review will describe novel neuroprotective effects of several morphinans in multiple inflammatory disease models. The potential therapeutic utility and underlying mechanisms of morphinan neuroprotection are discussed.

Topics: Animals; Anti-Inflammatory Agents; Encephalitis; Gliosis; Humans; Inflammation Mediators; Morphinans; Nerve Growth Factors; Neurodegenerative Diseases; Neuroprotective Agents

We recently demonstrated that endogenous prodynorphin-derived peptides mediate anticonvulsant, antiepileptogenic and neuroprotective effects via kappa opioid receptors (KOP). Here we show acute and delayed neurodegeneration and its pharmacology after local kainic acid injection in prodynorphin knockout and wild-type mice and neuroprotective effect(s) of KOP activation in wild-type mice. Prodynorphin knockout and wild-type mice were injected with kainic acid (3 nmoles in 50 nl saline) into the stratum radiatum of CA1 of the right dorsal hippocampus. Knockout mice displayed significantly more neurodegeneration of pyramidal cells and interneurons than wild-type mice 2 days after treatment. This phenotype could be mimicked in wild-type animals by treatment with the KOP antagonist GNTI and rescued in knockout animals by the KOP agonist U-50488. Minor differences in neurodegeneration remained 3 weeks after treatment, mostly because of higher progressive neurodegeneration in wild-type mice compared with prodynorphin-deficient animals. In wild-type mice progressive neurodegeneration, but not acute neuronal loss, could be mostly blocked by U-50488 treatment. Our data suggest that endogenous prodynorphin-derived peptides sufficiently activate KOP receptors during acute seizures, and importantly in situations of reduced dynorphinergic signaling-like in epilepsy-the exogenous activation of KOP receptors might also have strong neuroprotective effects during excitotoxic events.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; CA1 Region, Hippocampal; Enkephalins; Guanidines; Humans; Interneurons; Kainic Acid; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphinans; Neurodegenerative Diseases; Protein Precursors; Pyramidal Cells; Receptors, Opioid, kappa; Seizures