Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes

Sakitama, Katsuhiko; Ozawa, Yoshihito; Aoto, Naomi; Tomita, Hiroshi; Ishikawa, M.

doi:10.1016/s0014-2999(97)01289-2

Cited by 18 publications

(10 citation statements)

References 17 publications

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“…Lanperisone is a modified form of tolperisone, which was developed as a muscle relaxant. 11 Lanperisone can selectively kill K-Ras-mutant mouse embryonic fibroblasts through the induction of ROS, which is mediated through iron and Ras/RAF/MEK/ERK signaling ( Figure 1d). In vivo, lanperisone also showed efficacy against tumor growth in a K-Ras-driven mouse model of lung cancer.…”

Section: Morphologymentioning

confidence: 99%

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Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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Section: Morphologymentioning

confidence: 99%

“…12 The exact mechanism responsible for lanperisone-induced ROS generation is not known, but preliminary results suggest that it occurs through the perturbation of voltage-gated ion channels. 11 Sulfasalazine. Sulfasalazine is broadly used to treat chronic inflammation in the gut, joints, and retina.…”

Section: Morphologymentioning

confidence: 99%

Ferroptosis: process and function

et al. 2016

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“…Lanperisone, which is commonly used as a muscle relaxant, can induce ROS generation to selectively kill K- Ras -mutant mouse embryonic fibroblasts via ferroptosis signaling in vitro , and it can also inhibit tumor growth through inducing ferroptosis in a K- Ras -driven mouse model of lung cancer in vivo ( 194 , 217 ). However, the underlying mechanism of lanperisone-induced ROS generation is still unknown.…”

Section: The Role Of Caspase-independent Regulated Necrosis In Cancermentioning

confidence: 99%

Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management

et al. 2021

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Regulated necrosis is an emerging type of cell death independent of caspase. Recently, with increasing findings of regulated necrosis in the field of biochemistry and genetics, the underlying molecular mechanisms and signaling pathways of regulated necrosis are gradually understood. Nowadays, there are several modes of regulated necrosis that are tightly related to cancer initiation and development, including necroptosis, ferroptosis, parthanatos, pyroptosis, and so on. What’s more, accumulating evidence shows that various compounds can exhibit the anti-cancer effect via inducing regulated necrosis in cancer cells, which indicates that caspase-independent regulated necrosis pathways are potential targets in cancer management. In this review, we expand the molecular mechanisms as well as signaling pathways of multiple modes of regulated necrosis. We also elaborate on the roles they play in tumorigenesis and discuss how each of the regulated necrosis pathways could be therapeutically targeted.

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“…It possesses relatively few side effects in humans (Dulin et al, 1998). Other propiophenone muscle relaxants include 1-(4-ethylphenyl)-2-methyl-3-(1-piperidinyl)-1-propanone hydrochloride (eperisone), which is also a registered drug (Bose, 1999), and (Ϫ)-2-(R)-methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-propanone hydrochloride (lanperisone; Sakitama et al, 1997) and 1-(4-ethylphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone hydrochloride (inaperisone; Morikawa et al, 1992), two agents that had been tested in human phase III studies but not introduced into the clinical practice. 1- dimethylsilylmethyl]piperidine hydrochloride (silperisone), a sila analog of tolperisone (Farkas et al, 2005), has been shown in mice to have better separation between the desirable effects (i.e., reduction of abnormally increased muscle activity in various models) and anticipated undesirable effects (i.e., central nervous system depression and impairment of voluntary motor control) than currently available centrally acting muscle relaxant drugs.…”

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confidence: 99%

Tolperisone-Type Drugs Inhibit Spinal Reflexes via Blockade of Voltage-Gated Sodium and Calcium Channels

Kocsis

Farkas²,

Fodor³

et al. 2005

J Pharmacol Exp Ther

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The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50 -400 M), eperisone, lanperisone, inaperisone, and silperisone (25-200 M) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100 -800 M) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3 H]batrachotoxinin A 20-␣-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisonetype muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.2-Methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride (tolperisone) is an old, centrally acting muscle relaxant drug that is mainly used for treating muscle spasticities of neurological origin and painful muscle spasms due to rheumatologic conditions. Besides being an effective antispastic agent (Pratzel et al., 1996;Dulin et al., 1998), tolperisone also has analgesic activity in rodents (Sakaue et al., 2004) and in humans (Svensson et al., 2003). It possesses relatively few side effects in humans (Dulin et al., 1998). Other propiophenone muscle relaxants include 1-(4-ethylphenyl)-2-methyl-3-(1-piperidinyl)-1-propanone hydrochloride (eperisone), which is also a registered drug (Bose, 1999), and (Ϫ)-2-(R)-methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-propanone hydrochloride (lanperisone; Sakitama et al., 1997) and 1-(4-ethylphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone hydrochloride (inaperisone; Morikawa et al., 1992), two agents that had been tested in human phase III studies but not introduced into the clinical practice. 1-[(4-Fluorobenzyl)dimethylsilylmethyl]piperidine hydrochloride (silperisone), a sila analog of tolperisone (Farkas et ...

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Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes

Cited by 18 publications

References 17 publications

Ferroptosis: process and function

Ferroptosis: process and function

Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management

Tolperisone-Type Drugs Inhibit Spinal Reflexes via Blockade of Voltage-Gated Sodium and Calcium Channels

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