WO2020237080A1 - Thérapie de modulation mitochondriale non invasive pour un accident vasculaire cérébral - Google Patents

Thérapie de modulation mitochondriale non invasive pour un accident vasculaire cérébral Download PDF

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WO2020237080A1
WO2020237080A1 PCT/US2020/034052 US2020034052W WO2020237080A1 WO 2020237080 A1 WO2020237080 A1 WO 2020237080A1 US 2020034052 W US2020034052 W US 2020034052W WO 2020237080 A1 WO2020237080 A1 WO 2020237080A1
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nir
light
hours
wavelength
dual
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Maik Huettemann
Thomas H. SANDERSON
Christos D. STRUBAKOS
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Wayne State University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00345—Vascular system
    • A61B2018/00404—Blood vessels other than those in or around the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00434—Neural system
    • A61B2018/00446—Brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B2018/2065—Multiwave; Wavelength mixing, e.g. using four or more wavelengths
    • A61B2018/207—Multiwave; Wavelength mixing, e.g. using four or more wavelengths mixing two wavelengths
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N2005/002—Cooling systems
    • A61N2005/005—Cooling systems for cooling the radiator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared

Definitions

  • the present disclosure generally relates to near-infrared light (NIR) treatment, including NIR treatment of ischemic stroke.
  • NIR near-infrared light
  • Stroke is one of the leading causes of death and disability in the Western world and accounts for approximately 1 in 20 deaths in the United States.
  • Ischemic stroke occurs due to occlusion of an intracranial artery generally resulting in rapid and cytotoxic reductions in blood flow to the brain parenchyma.
  • approved treatments for ischemic stroke include rapid restoration of blood flow (i.e., reperfusion or reperfusion phase) either by pharmacological or surgical modalities. While patient outcomes have improved due to these interventions, a substantial amount of tissue damage may occur during the reperfusion phase.
  • ROS reactive oxygen species
  • Figure 1 illustrates exemplary blood flow during stroke ischemia and following reperfusion
  • Figure 2 illustrates an exemplary analysis of cerebral injury in an acute reperfusion phase
  • Figure 3 illustrates an exemplary infarct in a chronic phase of post-stroke reperfusion injury
  • Figure 4 illustrates exemplary relative cerebral blood flow during ischemia and following approximately 4-hour NIR treatment
  • Figure 5 illustrates exemplary infarct volumes in the acute phase of stroke with NIR treatment for approximately 4 hours
  • FIG. 6 illustrates exemplary T2 weighted images (T2WI) of exemplary infarct volumes during the chronic phase of stroke.
  • the present invention provides a method for treating ischemia-reperfusion injury associated with stroke (e.g., focal stroke).
  • Ischemic stroke is typically caused by occlusion of an intracranial artery.
  • ischemic stroke is often associated with a longer ischemic period before the occlusion in a patient is removed by medical intervention.
  • the longer ischemic period results in more severe tissue damages during the reperfusion stage, which increases the difficulty of achieving substantial protection by treatment.
  • the present invention identifies a noninvasive method of treating ischemic stroke by applying infrared light (IRL) to affected tissue for an extended duration.
  • IDL infrared light
  • Example 1 A method of reducing ischemia-reperfusion injury in a subject having a stroke, the method comprising applying light to tissue subject to ischemia-reperfusion injury for at least 3 hours (e.g., at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, or at least 60 hours) contemporaneous with and/or after the onset of ischemia-reperfusion injury thereby to reduce the extent of ischemia-reperfusion injury, wherein the light applied comprises light having wavelengths in each of the ranges of 730-770 nm and 930-970 nm.
  • the light applied comprises light having wavelengths in each of the ranges of 730-770 nm and 930-970 nm.
  • Example 2 The method of example 1, wherein the light is applied to the tissue for 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, or 60 hours contemporaneous with and/or after the onset of ischemia-reperfusion injury.
  • Example 3 The method of example 1 or 2, wherein the injury occurs during the acute phase of stroke.
  • Example 4 The method of any one of examples 1-3, wherein the injury occurs during the chronic phase of stroke.
  • Example 5 The method of any one of examples 1-4, wherein the illumination reduces the volume of tissue exhibiting an infarct by at least 30%, 40%, 50%, or 60% relative to a subject that has not been subject to the illumination.
  • Example 6 The method of any one of examples 1-5, wherein the light application has wavelengths of about 750 nm and about 950 nm.
  • the term“about” indicates deviations of up to 1% above and up to 1% below a given value.
  • Example 7 The method of any one of examples 1-5, wherein the light application has wavelengths of about 750 nm and about 940 nm.
  • the term“about” indicates deviations of up to 1% above and up to 1% below a given value.
  • Example 8 The method of any one of examples 1-7, wherein the light is substantially free of a wavelength of 810 nm and/or 808 nm.
  • the term“substantially free” indicates that the intensity of the light at the specified wavelength is no greater than 10% of the greater of the maximum intensity of in the range of 730-770 nm or that in the range of 930- 970 nm.
  • the term“substantially free” indicates that the intensity of the light at the specified wavelength is no greater than 5% of the greater of the maximum intensity of in the range of 730-770 nm or that in the range of 930-970 nm.
  • Example 9 The method of any one of examples 1-8, wherein the light is applied prior to the onset of the reperfusion injury.
  • Example 10 The method of any one of examples 1-9, wherein the light is applied in multiple, separate time periods.
  • Example 11 The method of example 10, wherein the light is applied in at least 2 (e.g., at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10) time periods.
  • Example 12 The method of example 11, wherein the light is applied in 2, 3, 4, 5, 6, 7, 8, 9, or 10 time periods.
  • Example 13 The method of example 11 or 12, wherein at least two of the time periods have the same time duration.
  • Example 14 The method of any one of examples 10-13, wherein all the time periods have the same time duration.
  • Example 15 The method of any one of examples 10-14, wherein the total duration of the light applied to the tissue is at least 3 hours (e.g., at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, or at least 60 hours).
  • the total duration of the light applied to the tissue is at least 3 hours (e.g., at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, or at least 60 hours).
  • Example 16 The method of any one of examples 10-15, wherein the total duration of the light applied to the tissue is 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, or 60 hours.
  • Example 17 The method of any one of examples 1-16, wherein the light is generated by one or more light emitting diodes.
  • Example 18 The method of any one of examples 1-17, wherein the light is generated by one or more laser diodes.
  • Example 19 The method of any one of examples 1-18, wherein the light has a fluence in the range of 5 mW to 80 mW (e.g., 0.1-50 mW, 0.1-20 mW, 0.1-10 mW, 0.1-5 mW, 0.1-1 mW, 1-50 mW, 1-20 mW, 1-10 mW, or 1-5 mW).
  • 5 mW to 80 mW e.g., 0.1-50 mW, 0.1-20 mW, 0.1-10 mW, 0.1-5 mW, 0.1-1 mW, 1-50 mW, 1-20 mW, 1-10 mW, or 1-5 mW.
  • Example 20 The method of any of examples 1-19, wherein the light has an irradiance in the range of 2 mW/cm 2 to 32 W/cm 2 (e.g., 50 mW/cm 2 to 2 W/cm 2 , 100 mW/cm 2 to 1 W/cm 2 , 500 mW/cm 2 -5 W/cm 2 , or 200-800 mW/cm 2 ).
  • the light has an irradiance in the range of 2 mW/cm 2 to 32 W/cm 2 (e.g., 50 mW/cm 2 to 2 W/cm 2 , 100 mW/cm 2 to 1 W/cm 2 , 500 mW/cm 2 -5 W/cm 2 , or 200-800 mW/cm 2 ).
  • Example 21 The method of any of examples 1-20, wherein the light has an irradiance lower than or equal to 5 W/cm 2 (e.g., lower than or equal to 2 W/cm 2 , or lower than or equal to 1 W/cm 2 ).
  • Example 22 The method of any of examples 1-21, wherein the light has an irradiance of about 10 mW/cm 2 , 20 mW/cm 2 , 50 mW/cm 2 , 100 mW/cm 2 , 200 mW/cm 2 , 400 mW/cm 2 , or 800 mW/cm 2 .
  • the term“about” indicates deviations of up to 10% above and up to 10% below a given value.
  • Example 23 The method of any of examples 1-22, wherein the light has a power density in the range of 0.01-0.1 mW/cm 2 , 0.1-1 mW/cm 2 , 0.5-5 mW/cm 2 , or 3-5 mW/cm 2 at the tissue.
  • Example 24 The method of any one of examples 1-23, wherein the stroke is focal stroke.
  • Example 25 The method of any one of examples 1-24, wherein the stroke is ischemic stroke.
  • Example 26 The method of example 25, wherein the duration of ischemia of the stroke is at least 30 minutes, at least 1 hour, or at least 2 hours.
  • COX cyclooxygenase
  • ETC mitochondrial electron transport chain
  • COX activity can be reduced by applying specific inhibitory NIR wavelengths (e.g., 750 nm, 950 nm, and the combination thereof).
  • inhibitory NIR wavelengths e.g., 750 nm, 950 nm, and the combination thereof.
  • Reduction of COX activity by inhibitory NIR leads to transient, reversible reductions in both mitochondrial respiration, and the mitochondrial membrane potential, and subsequent attenuation of superoxide production.
  • irradiation with inhibitory NIR wavelengths salvage neurons following oxygen glucose deprivation or glutamate exposure.
  • the effect of inhibitory NIR wavelengths in the setting of acute ischemic stroke which differs in the pathological evolution from global brain ischemia, has been investigated.
  • tPA tissue plasminogen activator
  • mechanical thrombectomy i.e., pharmaceutical or mechanical/surgical
  • NIR therapy would directly target salvageable tissue that succumbs to injury following reperfusion.
  • Brain injury was quantified by delineating infarct volume using diffusion weighted imaging (DWI) during early reperfusion and T2 weighted image (T2WI) at late reperfusion. Further, to increase rigor, incorporation of the ‘area at risk’ of infarction (i.e., volume of brain rendered ischemic during MCAO, derived from perfusion weighted images (PWI)) was introduced as a covariate in the analysis.
  • DWI diffusion weighted imaging
  • T2WI T2 weighted image
  • NIR treatment limits infarct size expansion in the early acute phase following stroke (e.g., 24 hours following restoration of blood flow). Additionally, another goal was to determine whether the positive effects of NIR treatment would persist as neuroprotection in late chronic phases of reperfusion (e.g., 7 and 14 days after ischemia).
  • LEDs Light emitting diodes
  • Diodes were mounted on heat sinks (e.g., black aluminum, 47x20 for LED array 60 chips) together with a fan (e.g., Evercool) operated in reverse mode.
  • Diodes were calibrated with an optical power meter (e.g., 842-PE) and operated with an energy density of approximately 200 mW/cm 2 .
  • mice were utilized in this model to provide a reproducible infarct, omitting changes in estrogen levels in females as another variable.
  • Animals were anesthetized with isoflurane (e.g., 5% induction, 2% maintenance in a mix of 70% nitrous oxide, 30% oxygen).
  • Surgery was conducted at approximately the same time of day for each animal. Temperature was maintained at approximately 37°C using a homeothermic blanket (e.g., Harvard Apparatus).
  • a neck incision was made, and the external carotid was ligated.
  • a silicon coated tip monofilament suture (e.g., Doccol Corporation) was inserted in the external carotid and advanced into the internal carotid artery until it occluded the MCA.
  • the filament was secured in place and the rats were placed in a temperature- and humidity-controlled chamber (e.g., Tecniplast). Following ischemia, animals were re-anesthetized, the filament withdrawn, and NIR treatment was initiated. Animals were given subcutaneous buprenorphine (e.g., 0.015 mg/kg) and recovered in a temperature/humidity-controlled environment. Weight loss exceeding 10% was addressed with enhanced nutritional support (e.g., DietGel) and/or subcutaneous administration of approximately 5% dextrose in normal saline.
  • a temperature- and humidity-controlled chamber e.g., Tecniplast
  • Rats were randomly enrolled in NIR-treatment or untreated groups during MCAO, prior to reperfusion.
  • NIR was administered with combined COX-inhibitory wavelengths of approximately 750 nm and approximately 950 nm. Briefly, LEDs at approximately 200 mW/cm 2 were placed approximately 1.5 cm from the shaved scalp upon filament withdrawal and continued for approximately 120 minutes (Protocol 1) or approximately 240 minutes (Protocol 2). That is, a method of reducing an ischemic reperfusion injury due to an acute stroke included applying near-infrared (NIR) light to a brain tissue subject to acute ischemic reperfusion injury for two (2) hours (Protocol 1) and four hours (protocol 2) to reduce the ischemic reperfusion injury.
  • NIR near-infrared
  • MRI protocols were performed on a 7.0-Tesla, 20-cm bore superconducting magnet (e.g., ClinScan; Bruker, Düsseldorf, Germany) with a Siemens console. Animals were anesthetized with isoflurane. Pulsed ASL (PWI) images were acquired according to the following exemplary sequence parameters: Relaxation time (TR) of 3500 ms; and echo time (TE) of 16 ms; field-of-view (FoV) read 35.0 mm; FoV phase 81.3%; distance factor 25%; slice thickness 2.0 mm; 4 slices.
  • TR Relaxation time
  • TE echo time
  • FoV field-of-view
  • DWI sequence was conducted according to the following exemplary parameters: TR 10000 ms; TE 50 ms; FoV read 32.0 mm; FoV phase 100.0%; distance factor 0%; slice thickness 0.5 mm; 32 slices.
  • T2WI was acquired according to the following exemplary parameters: TR 3530 ms; TE 38 ms; FoV read 32 mm; FoV phase 100.0%; distance factor 0%; slice thickness 1.0 mm; 24 slices.
  • Relative cerebral blood flow in the MCA territory during ischemia and reperfusion was calculated as previously described.
  • voxel intensity in ipsilateral and contralateral hemispheres was averaged across coronal slices of the MCA territory using ImageJ, giving the average relative cerebral blood flow (relCBF) voxel intensity value.
  • the boundary between hypoperfused and physiologically perfused brain tissue was identifiable on the relCBF.
  • CBF was calculated for both hemispheres giving cerebral blood flow rates in mL/lOOg/min.
  • Brains were traced from PWI of each animal during ischemia and following treatment (or matched time-points in untreated controls). Infarct volumes were computed using the semi-automated segmentation tool in Analyze 11.0 (e.g., Biomedical Imaging Resource, Mayo Clinic).
  • Seed points were set in the middle of the hyperintense MCA territory on a single slice and thresholds based on voxel intensity were set by the software until the injured region was outlined. The accuracy of the software generated outline was confirmed by a blinded investigator, then the software applied the exemplary threshold parameters to all slices within a sequence. This process provided an automated and unbiased calculation of the area within each slice. All the slices in the brain were summated then multiplied by the area thickness to generate infarct volume in mm 3 .
  • FIG. 1 illustrates exemplary relative blood flow during cerebral ischemia and following reperfusion.
  • an experimental protocol 100 for pulsed arterial spin labeling (PWI) imaging is shown.
  • exemplary PWI images 102 during ischemia and from both groups are shown following reperfusion indicating reduction of blood flow in the ipsilateral hemisphere during ischemia and restoration of blood flow during reperfusion.
  • FIG. 2 an exemplary analysis of cerebral injury in the acute reperfusion phase I is shown.
  • an exemplary experimental design 200 for measuring early phase outcomes is shown.
  • Exemplary diffusion weighted imaging (DWI) images 202 were obtained and no significant difference in infarct volume was seen between NIR treated and control animals after 2 hours of treatment.
  • DWI diffusion weighted imaging
  • NIR treated MCAO rats showed an exemplary 21% reduction of infarct volume.
  • An exemplary at risk area analyzed (see, e.g., Figure 2, 202) by PWI at 1-hour ischemia (x-axis) and DWI hyperintensity volume (y-axis) 2 hours and 24 hours following reperfusion is illustrated. This indicates that the regression relationship between infarct volume and area at risk for NIR- treated animals was below the relationship observed in controls.
  • NIR-treated animals showed a significant reduction of approximately 21% in DWI hyperintensity volume when compared with untreated controls: 317 vs. 399 mm 3 , p ⁇ 0.05 (see, e.g., Figure 2, 202).
  • Repeated measures ANOVA revealed an overall, significant increase in DWI-hyperintensity at 24 vs. 2 hours of reperfusion and a significant difference between NIR- treated and untreated groups at 24 hours of reperfusion.
  • ANCOVA incorporating‘area at risk’ (volume of brain rendered ischemic during MCAO, delineated by the volume of flow deficit identified by PWI) as a covariate in the analysis of infarct size.
  • area at risk volume of brain rendered ischemic during MCAO, delineated by the volume of flow deficit identified by PWI
  • ANCOVA revealed no difference in the regression relationship between DWI hyperintensity volume and area at risk between cohorts (p>0.05). This suggests that no measurable treatment effect at this early timepoint.
  • FIG. 3 an exemplary cerebral infarct in chronic phase of post-stroke reperfusion injury is shown.
  • An exemplary experimental design 300 at 7- and 14- days following reperfusion is represented.
  • Exemplary T2-weighted imaging (T2WI)-images 302 of MCAO vs. MCAO with NIR treatment are shown.
  • T2WI T2-weighted imaging
  • MCAO MCAO
  • NIR treated MCAO rats showed an exemplary 25% reduction in infarct volume.
  • Significant reduction in infarct volume persisted at 14 days post stroke. Accordingly, not only are ischemic reperfusion injury reductions observable via an imaging modality (e.g., magnetic resonance) at 7 days, but also at 14 days.
  • an imaging modality e.g., magnetic resonance
  • regression relationship of PWI (area at risk) vs. infarct volume in MCAO vs. MCAO treated with NIR is illustrated. Accordingly, the exemplary regression relationship is shown between infarct volume and risk region for NIR- treated animals. This indicates that the regression relationship was below the relationship observed in controls.
  • NIR- treated animals maintained a significant reduction of approximately 25% in infarct size when compared to untreated controls (271 vs 363 mm 3 , *p ⁇ 0.05) that persisted at 14 days after MCAO (241 vs. 317 mm 3 , *p ⁇ 0.05, Figure 3, 302), with no significant change over time. That is, infarction had generally fully evolved by 7 days of reperfusion and neuroprotection persisted at the final time-point of 14 days post-stroke.
  • the volume of hyperintensity (infarct) expressed as a percentage of the at-risk volume of brain, averaged 64% vs. 73% in the respective NIR-treated vs. control groups at 7 days, and approximately 57% vs.
  • FIG. 4 exemplary relative cerebral blood flow during ischemia and following an exemplary 4-hour NIR treatment is shown.
  • An exemplary experimental design 400 is represented, as well as exemplary PWI images 402 during ischemia and from both groups following reperfusion, which indicate restoration of blood flow.
  • Protocol 2 the efficacy of extended 4-hour treatment was assessed using the analytical approach described in Protocol 1.
  • exemplary infarct volumes in the acute phase of stroke with NIR for four hours is shown.
  • An exemplary experimental design 500 is represented, as well as the exemplary images 502 of DWI four hours following reperfusion in NIR treated vs. control, indicating a significant reduction in infarct size of the NIR-treated animals compared to the controls at the end of the 4-hour treatment (which was maintained at 24 hours post-treatment).
  • An exemplary at-risk area during ischemia (PWI) vs. area of infarction (DWI) at four hours following reperfusion is quantified in the graphs 504 of Figure 5.
  • FIG. 6 represents this determination, showing T2WI of infarct volumes during the chronic phase of stroke.
  • An exemplary experimental design 600 is represented, along with exemplary images 602.
  • the images 602 indicate that the NIR treated showed an exemplary 52% reduction in infarct volume at 7- and 14-days following ischemia vs. untreated controls.
  • At risk area vs area of infarction at 7- and 14-days post reperfusion show significant reduction with NIR-treatment, as represented in the graphs 604 of Figure 6.
  • infarct size or ischemic reperfusion injury size that are observable via an imaging modality (e.g., magnetic resonance) at 7 days and 14 days.
  • an imaging modality e.g., magnetic resonance
  • Observable in general may mean, for example, by the“naked eye” or indirectly via the imaging modality.
  • Ischemic stroke generally accounts for about approximately 9% of deaths globally and is generally the second leading cause of death following heart disease. Those who survive this debilitating disease often face a lifetime of neurological deficits and hence a drastic reduction in quality of life, including cognitive, emotional and functional impairments.
  • the gold standard for stroke treatment is generally considered to be the rapid restoration of blood flow.
  • timely reperfusion is, paradoxically, associated with a perpetuation of brain injury, due in part to the production of ROS during early reoxygenation.
  • Oxidative stress is a common pathological mechanism in many disease states and arises from an imbalance between ROS production and ROS scavenging. Once produced, ROS damage cells either directly, or through diverse and complex cell signaling cascades.
  • infarct volumes against area at risk are plotted, it is shown that for all groups in both Protocol 1 and Protocol 2 that the relationship between area at risk and area of infarction is linear. That is, infarct size is proportional to the area at risk. In addition, there was a downward shift in the regression relationship (with generally no difference in slope) for the NIR-treated cohorts versus controls. As such, it is determined that, over the full range of risk regions, the penumbra was salvaged with NIR treatment, resulting in smaller infarct volumes.
  • non-invasive partial inhibition of mitochondrial COX by dual -wavelength NIR treatment following acute (focal) stroke is accompanied by profound and sustained reductions in cerebral infarction.
  • the dual wavelength NIR treatment included exemplary wavelengths of 750 nm and 950 nm, other NIR wavelengths may be employed.
  • one wavelength may be selected from the range of 730-770 nm and the other wavelength may be selected from the range of 930-970 nm.
  • Methods discussed herein include removing a cerebral occlusion (such as an occlusion causing an acute stroke) either pharmacologically or mechanically. After or during removal, providing dual -wavelength near-infrared (NIR) light to mitochondrial electron transport chains in brain tissue to reduce reperfusion injury resulting from a stroke is begun.
  • the dual -wavelength NIR light may be provided for at least two hours, four hours, or more.
  • the dual wavelength NIR light may, for example, be selected from a range of 730-770 nm and a range of 930-970 nm. Further, the application of the applying the dual -wavelength NIR light may begin prior to an onset of reperfusion, during an onset of reperfusion, or after an onset of reperfusion. As one example, applying the NIR light may occur during the removal of the cerebral occlusion.
  • Such techniques or methods at least minimize post-stroke reperfusion injury (chronic phase).

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Abstract

L'invention concerne un procédé de réduction d'une lésion ischémique de reperfusion due à un accident vasculaire cérébral aigu. Le procédé comprend l'application d'une lumière proche infrarouge (NIR) d'au moins deux longueurs d'onde à un tissu cérébral soumis à une lésion ischémique de reperfusion pendant plus de deux (2) heures afin de réduire la lésion ischémique de reperfusion observable par l'intermédiaire d'une modalité d'imagerie au moins sept (7) jours après l'application de la lumière NIR.
PCT/US2020/034052 2019-05-21 2020-05-21 Thérapie de modulation mitochondriale non invasive pour un accident vasculaire cérébral WO2020237080A1 (fr)

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US20140371826A1 (en) * 2009-05-01 2014-12-18 Wayne State University Light therapy treatment
US20180304091A1 (en) * 2009-05-01 2018-10-25 Wayne State University Light therapy treatment
WO2020092729A1 (fr) * 2018-10-31 2020-05-07 Wayne State University Méthode et appareil de traitement par luminothérapie

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