Effects of dihydroergocriptine on mouse and rat resistance to acute anoxia: influence of repetition of treatment

Legeai, J.; Benharkate, M.; Duverger, Jp; Boulu, R

doi:10.1007/bf01991662

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…Unfortunately, multiple compounds targeting Na v 1.7 have failed in recent clinical trials. 41,56 Multiple theories underlie the difficulty or failure to pharmacologically target Na v 1.7, but undeniably a key determinant is the challenge to selectively target this channel without affecting other similar channels in the nervous system. In contrast to pharmacologically targeting the Na v 1.7 channel directly, we have demonstrated that indirect regulation of Na v 1.7, through preventing the addition of SUMO1 onto the Na v 1.7 interacting protein CRMP2, blocked Na v 1.7 functions and was antinociceptive.…”

Section: Discussionmentioning

confidence: 99%

Targeted transcriptional upregulation of SENP1 by CRISPR activation enhances deSUMOylation pathways to elicit antinociception in the spinal nerve ligation model of neuropathic pain

Gomez,

Allen,

Duran

et al. 2023

Pain

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The voltage-gated sodium channel NaV1.7 is an essential component of human pain signaling. Changes in NaV1.7 trafficking are considered critical in the development of neuropathic pain. SUMOylation of collapsin response mediator protein 2 (CRMP2) regulates the membrane trafficking and function of NaV1.7. Enhanced CRMP2 SUMOylation in neuropathic pain correlates with increased NaV1.7 activity. Pharmacological and genetic interventions that interfere with CRMP2 SUMOylation in rodents with neuropathic pain have been shown to reverse mechanical allodynia. Sentrin or SUMO-specific proteases (SENPs) are vital for balancing SUMOylation and deSUMOylation of substrates. Overexpression of SENP1 and/or SENP2 in CRMP2-expressing cells results in increased deSUMOylation and decreased membrane expression and currents of NaV1.7. Although SENP1 is present in the spinal cord and dorsal root ganglia, its role in regulating NaV1.7 function and pain is not known. We hypothesized that favoring SENP1 expression can enhance CRMP2 deSUMOylation to modulate NaV1.7 channels. In this study, we used a clustered regularly interspaced short palindromic repeats activation (CRISPRa) SENP1 lentivirus to overexpress SENP1 in dorsal root ganglia neurons. We found that SENP1 lentivirus reduced CRMP2 SUMOylation, NaV1.7–CRMP2 interaction, and NaV1.7 membrane expression. SENP1 overexpression decreased NaV1.7 currents through clathrin-mediated endocytosis, directly linked to CRMP2 deSUMOylation. Moreover, enhancing SENP1 expression did not affect the activity of TRPV1 channels or voltage-gated calcium and potassium channels. Intrathecal injection of CRISPRa SENP1 lentivirus reversed mechanical allodynia in male and female rats with spinal nerve injury. These results provide evidence that the pain-regulating effects of SENP1 overexpression involve, in part, the modulation of NaV1.7 channels through the indirect mechanism of CRMP2 deSUMOylation.

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Section: Discussionmentioning

confidence: 99%

Targeted transcriptional upregulation of SENP1 by CRISPR activation enhances deSUMOylation pathways to elicit antinociception in the spinal nerve ligation model of neuropathic pain

Gomez,

Allen,

Duran

et al. 2023

Pain

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“…In this respect, the effects of the ergot alkaloids which were observed, would be quite remarkable. A cere bral antihypoxic effect of DHEC, all the more marked when the brain is submitted to re peated anoxia, has thus been described pre viously [19]. In aged rats submitted to double ligation of the carotid arteries, as opposed to intact aged rats.…”

Section: Discussionmentioning

confidence: 99%

“…DHEC (0.1 mg/kg) or distilled water ( I ml/animal). The doses of DUET and DHEC used in these assays were chosen on the basis of previous pharmacological assays [19,29]. The last administration was carried out 2 h before sac rifice of the animals.…”

Section: Groups and Treatmentmentioning

confidence: 99%

Simultaneous Study of Cerebral Blood Flow, Vascular Bed and Deoxyglucose in Aged Rats

Rapin¹,

Poncin-Lafitte²,

Lespinasse³

1984

Pharmacology

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The influence of aging and the effects of treatment with dihydrogenated rye ergot alkaloid on cerebral hemodynamics and metabolism were studied in Long-Evans rats. Cerebral blood flow (CBF) was not affected by aging whereas the vascular bed and the uptake of deoxyglucose were significantly lower in aged than in young rats. 20 days after ligation of a carotid artery the blood flow on the same side of the brain, the vascular bed and the uptake of deoxyglucose were significantly lowered in aged rats as opposed to young rats. The second carotid artery was ligated 1 h before the animals were sacrificed: in the corresponding cerebral hemisphere the blood flow was found to be significantly lowered in young rats and even more so in aged rats. These results show that young rats are more likely to adapt to an acute or chronic circulatory deficiency than aged rats. Dihydroergocryptine (DHEC, 0.1 mg/kg/day for 5 days, p.o.) reduces CBF and the vascular bed in aged rats, as opposed to dihydroergotoxine (DHET, 5 × 0.1 mg/kg/day p.o.). The uptake of deoxyglucose was not influenced by the treatments. After ligation of the carotid arteries, treatment with DHEC and DHET induced an increase in CBF without any change in the vascular bed and, in the case of DHEC only, there was a significant increase in the uptake of deoxyglucose in the cerebral hemisphere submitted to acute circulatory deficiency. DHEC and DHET thus exerted significant effects on cerebral metabolism and hemodynamics in the aged rats after repeated oral treatment.

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The effects of dihydroergocryptine on the neurological and enzyme disorders induced by cerebral ischaemia in rats

Cahn¹,

Borzeix²,

Legeai³

1989

Resuscitation

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Effects of dihydroergocriptine on mouse and rat resistance to acute anoxia: influence of repetition of treatment

Cited by 3 publications

References 3 publications

Targeted transcriptional upregulation of SENP1 by CRISPR activation enhances deSUMOylation pathways to elicit antinociception in the spinal nerve ligation model of neuropathic pain

Targeted transcriptional upregulation of SENP1 by CRISPR activation enhances deSUMOylation pathways to elicit antinociception in the spinal nerve ligation model of neuropathic pain

Simultaneous Study of Cerebral Blood Flow, Vascular Bed and Deoxyglucose in Aged Rats

The effects of dihydroergocryptine on the neurological and enzyme disorders induced by cerebral ischaemia in rats

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