Use of mitochondrial division inhibitors and combinations comprising same
A technology of mitochondria and inhibitors, applied in drug combinations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc.
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[0149] The preparation method of the compound of formula (Ⅲ)
[0150] For the description of the compound of formula (III), see, for example, WO 2012 / 158624, the relevant content of which is incorporated by reference in its entirety. Those skilled in the art will understand that the compound of formula (III) may be, for example, a polypeptide or a peptide conjugate. Methods for the preparation of polypeptides and peptide conjugates are well known to those skilled in the art. For example, methods for preparing compounds of formula (III) may include, but are not limited to: using recombinant DNA technology to obtain nucleic acids encoding compounds of formula (III) and expressing the nucleic acids in suitable systems (such as host cells); chemical synthesis; using A linker containing an active group covalently conjugates the mitochondrial fission inhibitory peptide to the penetrating peptide. In some embodiments, P110 is commercially available.
[0151] 2. Opioid analgesic de...
Embodiment 1
[0261] Example 1: Mdivi-1 and P110 inhibit mitochondrial fragmentation in dopaminergic neurons in the ventral tegmental area of the midbrain after chronic morphine use
[0262] 1.1 Long-term use of morphine increases the mitochondrial fragmentation of dopaminergic neurons in the ventral tegmental area of the midbrain
[0263] Inject a Cre-dependent mitochondrial fluorescent tracer virus into the ventral tegmental area (VTA) of the midbrain of TH-Cre mice to achieve specific tracer of the mitochondria of VTA dopamine neurons; two weeks after virus expression, the mice were divided into For the morphine group (Mor) and the control group (Sal), morphine was administered in ascending doses (morphine group) or an equal volume of normal saline (control group) in the rearing cage. Nine hours after the last dose-increasing injection, the brain tissue of the mouse was taken, fixed and cut into brain slices, and the dendrites of neurons in the ventral tegmental area (VTA) of the mou...
Embodiment 2
[0272] Example 2: Mdivi-1 and P110 inhibit the analgesic tolerance caused by long-term use of morphine and enhance the analgesic effect
[0273] Put the wild-type mice in the hot plate apparatus, set the temperature to 50°C, use the mice to lick their hind feet or jump as observation indicators, measure the pain threshold of the mice, pre-select the mice with pain thresholds within 30s, and carry out the experiment .
[0274] The mice were randomly divided into Mdivi-1 groups (Mor+Mdivi-1(12.5mg / kg), Mor+Mdivi-1(25mg / kg), Mor+Mdivi-1(50mg / kg), Mor+Mdivi-1 (100mg / kg)) and the control group (Mor+vehicle), the mice were injected intraperitoneally with 12.5, 25, 50 or 100mg / kg Mdivi-1 (Mdivi-1 group) or an equal volume of corn oil (control group), One hour after the injection, morphine was subcutaneously injected into the back (10 mg / kg each time, once a day), and then the pain threshold of the mice was measured for 6 consecutive days.
[0275] Or the mice were randomly divided ...
PUM
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