scholarly journals Impact of Age and Sex on α-Syn (α-Synuclein) Knockdown-Mediated Poststroke Recovery

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3138-3141
Author(s):  
Bharath Chelluboina ◽  
Taehee Kim ◽  
Suresh L. Mehta ◽  
Joo-Yong Kim ◽  
Saivenkateshkomal Bathula ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Artery Occlusion ◽  
Motor Deficits ◽  
Ischemic Brain ◽  
Therapeutic Opportunity ◽  
Interfering Rna ◽  
Cerebral Artery Occlusion ◽  
Age And Sex

Background and Purpose: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. Methods: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. Results: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. Conclusions: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.

scholarly journals Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage

2017 ◽  
Vol 38 (6) ◽  
pp. 1060-1069 ◽  
Author(s):  
Abraham Cisneros-Mejorado ◽  
Miroslav Gottlieb ◽  
Asier Ruiz ◽  
Juan C Chara ◽  
Alberto Pérez-Samartín ◽  
...  
Keyword(s):  
Brain Damage ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Atp Release ◽  
Artery Occlusion ◽  
Ruthenium Red ◽  
Ischemic Brain ◽  
Knock Out ◽  
Cerebral Artery Occlusion ◽  
Cortical Slices

Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.

scholarly journals No Role for Interleukin-18 in Acute Murine Stroke-Induced Brain Injury

2003 ◽  
Vol 23 (5) ◽  
pp. 531-535 ◽  
Author(s):  
Rachel D. Wheeler ◽  
Herve Boutin ◽  
Omar Touzani ◽  
Giamal N. Luheshi ◽  
Kiyoshi Takeda ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Brain Damage ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Interleukin 18 ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

There is now extensive evidence to show that the cytokine interleukin-1 (IL-1) contributes directly to reversible and permanent ischemic brain damage in rodents. Because interleukin-18 (IL-18) shares many structural and functional similarities with IL-1, the authors tested the hypothesis that IL-18 contributes directly to ischemic brain damage in mice exposed to focal, reversible (15-minute or 30-minute) middle cerebral artery occlusion. IL-18 expression was not induced acutely by middle cerebral artery occlusion, and deletion of the IL-18 gene (IL-18 knockout mice) did not affect infarct volume. The present results suggest that IL-18 does not contribute to acute ischemic brain damage.

scholarly journals Postischemic Administration of AK275, a Calpain Inhibitor, Provides Substantial Protection against Focal Ischemic Brain Damage

1994 ◽  
Vol 14 (4) ◽  
pp. 537-544 ◽  
Author(s):  
Raymond T. Bartus ◽  
Keith L. Baker ◽  
Angie D. Heiser ◽  
Sean D. Sawyer ◽  
Reginald L. Dean ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Calpain Inhibitor ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Diastereomeric Mixture ◽  
Cerebral Artery Occlusion

Experiments were conducted to determine whether a potent, reversible calpain inhibitor could reduce the cortical ischemic brain damage associated with focal ischemia in the rat. AK275 (Z-Leu–Abu–CONH–CH2CH3), the active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any drug effect. Focal ischemia was induced using a variation of the middle cerebral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μ M (perfused supracortically at 4 μl/h for 21 h). Moreover, a 75% reduction in infarct volume was observed when initiation of drug treatment was delayed for 3 h postocclusion. Our data further support an important role of calpain in ischemia-induced neuropathology and suggest that calpain inhibitors may provide a unique and potentially powerful means of treating stroke and other ischemic brain incidents.

scholarly journals Exacerbation of Ischemic Brain Damage by Localized Striatal Injection of Interleukin-1β in the Rat

1998 ◽  
Vol 18 (8) ◽  
pp. 833-839 ◽  
Author(s):  
R. Paul Stroemer ◽  
Nancy J. Rothwell
Keyword(s):  
Body Temperature ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Brain Damage ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Ischemic Damage ◽  
Ischemic Brain ◽  
Site Of Action ◽  
Cerebral Artery Occlusion

Interleukin-1β (IL-1β) has been implicated in ischemic brain damage. The site of action of IL-1β in such damage is not known, but we have demonstrated previously that injection of the interleukin-1 receptor antagonist (IL-1ra) in the striatum but not the cortex of rats inhibits damage caused by permanent middle cerebral artery occlusion. The present study investigated the site of action of IL-1β on ischemic damage by examining the effects of intracerebroventricular, striatal, or cortical injection of recombinant IL-1β at the onset of permanent middle cerebral artery occlusion in the rat. Intracerebroventricular injection of IL-1β (2.5 ng) significantly increased infarct volume in the striatum (35%, P < 0.0001) and in the cortex (44%, P < 0.0001) compared with vehicle treatment. Direct injection of IL-1β into the striatum also increased infarct volume in both the striatum (36%, P < 0.0001) and the cortex (38%, P < 0.0001), whereas injection of IL-1β into the cortex failed to affect infarct volume in either the striatum or the cortex. Cortical injection of a higher dose of IL-1β (20 ng) also failed to affect ischemic damage in either the striatum or the cortex. Injection of IL-1β into the striatum contralateral to the infarction had no effect on striatal damage in the ischemic hemisphere, but did increase cortical damage by 18% ( P < 0.0001). In separate groups of animals, IL-1β (2.5 ng) was injected into either the striatum or the cortex, and body temperature was recorded continuously in conscious free-moving animals by remote telemetry. Injection of IL-1β at either site failed to influence body temperature, suggesting that exacerbation of brain damage by striatal injection of IL-1β is not caused by effects on body temperature. These results imply that IL-1β exacerbates ischemic damage by specific actions in the striatum where it can influence damage at distant sites in the cortex.

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

2005 ◽  
Vol 25 (6) ◽  
pp. 748-762 ◽  
Author(s):  
Takashi Mori ◽  
Terrence Town ◽  
Jun Tan ◽  
Narito Tateishi ◽  
Takao Asano
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Ischemic Brain ◽  
Human Apolipoprotein ◽  
Beneficial Effects ◽  
Neurologic Deficits ◽  
Significant Amelioration ◽  
Infarct Expansion ◽  
Cerebral Artery Occlusion

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we have shown that delayed infarct expansion and reactive astrocytosis after permanent middle cerebral artery occlusion (pMCAO) were markedly exacerbated in 4/4-KI mice as compared with 2/2- or 3/3-KI mice. Here, we probed the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using arundic acid (ONO-2506, Ono Pharmaceutical Co. Ltd), which is known to oppose astrocytic activation through its inhibitory action on S100B synthesis. In all of the KI mice, administration of arundic acid (10 mg/kg day, intraperitoneal, started immediately after pMCAO) induced significant amelioration of brain damage at 5 days after pMCAO in terms of infarct volumes (results expressed as the mean infarct volume (mm3) ±1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 16±2, 15±2, or 22±2; in the arundic acid groups: 11±2 ( P<0.001), 11±2 ( P<0.001), or 12±2 ( P<0.001), as compared with the vehicle groups), neurologic deficits, and S100/glial fibrillary acidic protein burden in the peri-infarct area. The beneficial effects of arundic acid were most pronounced in 4/4-KI mice, wherein delayed infarct expansion together with deterioration of neurologic deficits was almost completely mitigated. The above results support the notion that the apoE4 isoform exacerbates brain damage during the subacute phase of pMCAO through augmentation of astrocytic activation. Thus, pharmacological modulation of astrocytic activation may confer a novel therapeutic strategy for ischemic brain damage, particularly in APOE ɛ4 carriers.

scholarly journals Differential Effects of 17β-Estradiol upon Stroke Damage in Stroke Prone and Normotensive Rats

2004 ◽  
Vol 24 (3) ◽  
pp. 298-304 ◽  
Author(s):  
Hilary V Carswell ◽  
Deborah Bingham ◽  
Kirsty Wallace ◽  
M Nilsen ◽  
David I Graham ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Negative Effects ◽  
Spontaneously Hypertensive ◽  
Endogenous Estrogen ◽  
17Β Estradiol ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto ◽  
Cerebral Artery Occlusion

We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17β-estradiol (0.025mg or 0.25mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17β-estradiol levels for placebo and 17β-estradiol groups were as follows: WKY 0.025 mg 16.4 ± 8.5 (pg/mL, mean ± SD) and 25.85 ± 12.6; WKY 0.25 mg 18.2 ± 9.0 and 69.8 ± 27.4; SHRSP 0.25 mg 20.7 ± 8.8 and 81.0 ± 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17β-estradiol groups: SHRSP 0.025 mg 126.7 ± 15.3 mm3 (n = 6) and 114.0 ± 14.1 mm3 (n = 8) (not significant); SHRSP 0.25 mg 113.5 ± 22.3 mm3 (n = 8) and 129.7 ± 26.2 mm3 (n = 7) (not significant), respectively. In WKY, 17β-estradiol significantly increased infarct volume by 65% with 0.025mg dose [36.1 ± 20.7 mm3 (n = 8) and 59.7 ± 19.3 mm3 (n = 8) ( P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 ± 36.4 mm3 (n = 8) and 109.7 ± 6.7 mm3 (n = 4) ( P = 0.017)]. Thus, 17β-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17β-estradiol in clinical studies.

scholarly journals Reduction of Infarct Volume by Magnesium after Middle Cerebral Artery Occlusion in Rats

1991 ◽  
Vol 11 (6) ◽  
pp. 1025-1030 ◽  
Author(s):  
Yoshio Izumi ◽  
Simon Roussel ◽  
Elisabeth Pinard ◽  
Jacques Seylaz
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Mca Occlusion ◽  
Cerebral Artery Occlusion ◽  
Hyperglycemic Effect

The effects of magnesium, an endogenous inhibitor of calcium entry into neurons, upon ischemic brain damage were investigated using a well-characterized model of focal cerebral ischemia in rats. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride transcardiac perfusion 48 h after middle cerebral artery (MCA) occlusion. The area of ischemic damage was quantified by image analysis in coronal sections taken every 0.5 mm. MgCl2 (1 mmol/kg) was injected intraperitoneally just after MCA occlusion and again 1 h later. Posttreatment with MgCl2 (16 control and 16 treated rats) significantly reduced the cortical infarct volume. Compensation for the hyperglycemic effect of MgCl2 with insulin (17 rats) further reduced the infarct volume in the neocortex. No systemic effects of either treatment could account for the observed neuroprotection.

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