WO1994008612A1 - Nouveau procede de protection du systeme nerveux central contre les lesions produites par l'alteration cerebrovasculaire ou neuronale - Google Patents

Nouveau procede de protection du systeme nerveux central contre les lesions produites par l'alteration cerebrovasculaire ou neuronale Download PDF

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Publication number
WO1994008612A1
WO1994008612A1 PCT/US1993/010098 US9310098W WO9408612A1 WO 1994008612 A1 WO1994008612 A1 WO 1994008612A1 US 9310098 W US9310098 W US 9310098W WO 9408612 A1 WO9408612 A1 WO 9408612A1
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WO
WIPO (PCT)
Prior art keywords
histidine
nervous system
central nervous
cerebrovascular
recited
Prior art date
Application number
PCT/US1993/010098
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English (en)
Inventor
Peter G. Thomas
Original Assignee
Thomas Peter G
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thomas Peter G filed Critical Thomas Peter G
Priority to AU53654/94A priority Critical patent/AU5365494A/en
Publication of WO1994008612A1 publication Critical patent/WO1994008612A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • the present invention is related generally to methods of protecting cerebral tissues against ischemic damage and vasospasm. More particularly, the present invention is related to a new method of protecting central nervous system (CNS) cells or tissues against ischemic neurological deficits, vasospasm or neuronal insult.
  • CNS central nervous system
  • SAH aneurysmal subarachnoid hemorrhage
  • the prevention or reversal of neuronal ischemic deficits from vasospasm can be considered in three categories: First, measures to improve blood flow by altering the rheological characteristics of the blood; second, measures to improve oxygen delivered to the cerebral tissues; and third, hemodynamic measures to increase cerebral blood flow.
  • these approaches are generally complicated, hazardous, and non-physiological and should be considered primarily interim solutions until measures for specifically preventing or reversing the arterial narrowing can be developed (Kassell et al, vide supra) .
  • an object of the present invention to provide an effective method of controlling damage to the central nervous system resulting from such conditions as ischemic neurological deficits, vasospasm, inflammation, infection, injury, or changes in the level or function of neurotransmitters and the like.
  • a new method of protecting the central nervous system against or ameliorating damage resulting from, but not limited to, such conditions as ischemic neurological deficits, vasospasm, inflammation, injury, infection, or changes in the level or function of neurotransmitters comprising the step of administering a sufficient amount of histidine or its salts, derivatives, analogs, and the like, to the cells or tissues in the CNS susceptible to damage resulting from cerebrovascular, inflammatory, infectious or other neuronal insults, to protect against or ameliorate said damage.
  • Cerebrovascular or neuronal compromise means any change due to any cause in the normal condition or function of the cerebrovascular or neuronal cell or tissue in the central nervous system, and the resultant effect thereof. Some of such causes and effects have been mentioned elsewhere in this application.
  • protecting includes prevention, amelioration, reversal or in any manner controlling damage to any CNS cell or tissue where ischemia, vasospasm, infection, physical damage or other causes of impaired neuronal functions are involved.
  • the standard orphometric method employed in the study of vasospasm includes analysis of fixed histological arterial cross-sections to measure luminal diameters in animal models of chronic cerebral vasospasm as described in detail by Lehman et al, in Cerebral Vasospasm. ed. Robert H. Williams, Raven Press, New York, N.Y. pp 113- 117.
  • the ACSF consists of the following (in mM) : 110.2 NaCl, 2.9 KC1, 1.1 KH 2 P0 4 , 2.1 MgS0 4 , 1.8 CaCl 2 , 22.8 NaHC0 3 , 8.9 glucose.
  • the brains are first hemisected at the midline, and then one of the hemispheres was bisected in a horizontal plane followed by a sagittal section.
  • the superior-lateral quadrant of this dissection is placed on a tissue chopper and brain slices were cut in a coronal plane at a thickness of 400 mm.
  • Brain slices containing the parietal cortex at the level of the striatum are placed in a petri dish containing ACSF. Slices are then transferred to a holding chamber held at 35.5 C and maintained at interface with a humidified atmoshpere of 95% 0 2 : 5% C0 2 (i.e. normoxic conditions).
  • slices are transferred to a recording chamber as required.
  • a bipolar stimulating electrode is positioned under visual guidance near the layer IV - layer V border in the slice.
  • a glass microelectrode filled with 3 M NaCl (1-5 megaohm) is placed in layer III above the position of the stimulating electrode.
  • Stimuli are delivered once every fifteen seconds and the amplitude of evoked cortical potentials measured in response to a range of stimulation intensities.
  • stimuli are administered at an intensity adjusted to elicit a response of approximately 60% of the maximal amplitude.
  • Hypoxic conditions are achieved by substituting 99% N 2 for the normal 95% 0 2 :5% C0 in the atmosphere of the recording chamber.
  • the standard temperature in the recording chamber is 35.5 C.
  • a stable baseline of evoked responses is established under normoxic conditions for at least 15 minutes. Histidine (10 - 100 mM) or standard ACSF is then perfused for the remainder of the experiment. After 15 minutes of perfusion with histidine, hypoxic conditions are initiated. Hypoxic conditions were maintained until 10 minutes following the occurrence of hypoxic depolarization after which the slices are reoxygenated. Slices are monitored continuously for one hour following reoxygenation.
  • the neuroprotective effect of histidine is determined by comparing the recovery of evoked responses following hypoxia in control and histidine-treated slices.
  • Figure 1 shows the effect of histidine on SAH-induced vasospasm. The data clearly show the reversal of arterial constriction by histidine. Significantly pronounced effects were observed with dosages of 50 mg and 100 mg histidine administered 2x/day and 4x/day, respectively.
  • hypoxic parietal cortex slices were treated with histidine, increased synaptic transmission was observed (data not shown) .
  • histidine or its salts, derivatives or analogs can be administered in a pharmaceutically acceptable vehicle by any suitable route, e.g., intracerebrally into the cerebrospinal fluid or blood stream, intrathecally, intravenously, sublingually and the like.
  • histidine was provided as a free base in the experiments described herein, it could be easily provided as a salt (e.g., monohydrochloride monohydrate) or as a dipeptide.
  • Either L-, D- or DL-histidine could be used and any one of these isomeric forms could be administered in a preventive or therapeutic regimen.
  • histidine could be combined with other therapeutics, such as antibiotics, calcium channel blockers, anticoagulative, antiplatelet and thrombolytic agents, free radical scavengers, antibodies, other amino acids, and the like, for example heparin, warfarin, aspirin, TPA, streptokinase, APSAC, superoxide dismutase, catalase, mannitol, deferoxamine, nifedipine, verapamil, etc.
  • antibiotics such as antibiotics, calcium channel blockers, anticoagulative, antiplatelet and thrombolytic agents, free radical scavengers, antibodies, other amino acids, and the like, for example heparin, warfarin, aspirin, TPA, streptokinase, APSAC, superoxide dismutase, catalase, mannitol, deferoxamine, nifedipine, verapamil, etc.

Abstract

On protège le système nerveux central contre le vasospasme cérébral ou l'altération neuronale, ou on traite ces affections en administrant de l'histidine ou ses sels, ses dérivés ou analogues aux tissus ou aux cellules du système nerveux central. L'histidine pourrait également être combinée avec d'autres agents thérapeutiques.
PCT/US1993/010098 1992-10-22 1993-10-19 Nouveau procede de protection du systeme nerveux central contre les lesions produites par l'alteration cerebrovasculaire ou neuronale WO1994008612A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53654/94A AU5365494A (en) 1992-10-22 1993-10-19 New method of protecting central nervous system against damage resulting from cerebrovascular or neuronal compromise

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96473092A 1992-10-22 1992-10-22
US07/964,730 1992-10-22

Publications (1)

Publication Number Publication Date
WO1994008612A1 true WO1994008612A1 (fr) 1994-04-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/010098 WO1994008612A1 (fr) 1992-10-22 1993-10-19 Nouveau procede de protection du systeme nerveux central contre les lesions produites par l'alteration cerebrovasculaire ou neuronale

Country Status (2)

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AU (1) AU5365494A (fr)
WO (1) WO1994008612A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4045556A (en) * 1974-10-16 1977-08-30 Eberhard Schwertner Dipeptide derivatives, process for manufacture and pharmaceutical preparations
WO1986000812A1 (fr) * 1984-07-30 1986-02-13 Pharmacia Ab Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation
US4981691A (en) * 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
US5095027A (en) * 1991-02-28 1992-03-10 Clintec Nutrition Co. Method for treating reperfusion injury employing L-2-oxothiazolidine-4-carboxylic acid

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4045556A (en) * 1974-10-16 1977-08-30 Eberhard Schwertner Dipeptide derivatives, process for manufacture and pharmaceutical preparations
US4981691A (en) * 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
WO1986000812A1 (fr) * 1984-07-30 1986-02-13 Pharmacia Ab Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation
US5095027A (en) * 1991-02-28 1992-03-10 Clintec Nutrition Co. Method for treating reperfusion injury employing L-2-oxothiazolidine-4-carboxylic acid

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Publication number Publication date
AU5365494A (en) 1994-05-09

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