Compositions
An analog, dinucleoside polyphosphate technology, applied in the field of composition, can solve problems such as uncured and uncontrollable seizures
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Embodiment 1
[0198] In vivo data-AppCH 2 Antiepileptic activity of ppA in a mouse model of tuberous sclerosis
[0199] Tuberous sclerosis syndrome (TSC) is caused by a dominant mutation in the TSC1 or TSC2 tumor suppressor gene and is characterized by abnormal brain damage, that is, cortical nodules that are thought to contribute to the development of drug-resistant epilepsy Section. Tsc1 heterozygotes without nodules + / - The mice showed relapse and lived in the early postnatal period ( figure 1 with figure 2 ).
[0200] When the stable synthetic dinucleoside polyphosphate analogue AppCH 2 ppA was administered to Tsc1 by intraperitoneal (i.p.) injection at a dose of 100 μM (200 μl) (20 nmol; 1000 nmol / kg or 0.84 mg / kg of animal body weight) + / - In mice, there are basically complete anti-epileptic effects ( image 3 ). When using 30μM (200μl) (6nmol; 300nmol / kg or 0.25mg / kg of animal body weight) AppCH 2 ppA dose repeat the experiment ( Figure 4 ), the effect on epilepsy is partial.
Embodiment 2
[0202] In vitro data-AppCH 2 Antiepileptic activity of ppA in mouse cortical sections
[0203] Wild type and Tsc1 + / - The mice (P14~P16) were anesthetized, and their brains were quickly removed and placed in oxygenated ice-cold saline buffer. Before recording, the sections were incubated in artificial cerebrospinal fluid (ACSF). After in vitro administration of the slices, monitor AppCH 2 The effect of ppA administration. Untreated sections were also studied for control comparison (Figure 5). Slicing work shows: AppCH 2 ppA inhibited the onset of external electrical impulses on single cortical neurons and the entire animal.
Embodiment 3
[0205] In vitro data-AppCH 2 Antiepileptic activity of ppA in mouse hippocampal slices
[0206] The slices were prepared as described previously (Melnik S, Wright M, Tanner JA, Tsintsadze T, Tsintsadze V, Miller AD, Lozovaya N (2006) Diadenosine polyphosphate analogcontrols postsynaptic excitation in CA3-CA1synapses via a nitric oxide-dependent mechanism. J Pharmacol Exp Ther 318(2):579-588.doi:10.1124 / jpet.105.097642). Add tetrandrine (100μM) to the perfusion solution and remove Mg 2+ Induce spontaneous epileptiform events lasting 5-10 seconds ( Figure 7 ). In the first few minutes after the start of tetrandrine infusion, these events initially appeared at a low rate, and the rate gradually increased to reach a plateau frequency of about 6-8 events / 5 minutes within 20-30 minutes. ). Without Mg 2+ When the extracellular fluid of tetrandrine toxin continues to exist, it bursts at such a rate for at least 2 hours. After in vitro section administration, monitor AppCH 2 The effec...
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