Global Ischemia in Mice

Supplementary table 1: The search “Global ischemia in mice” in PubMed 19th January 2013 returned 623 results. 31 of the 623 papers were singled out as examples of the different ways of inducing GCI found in the available literature. For each study we report 10 different parameters which can influence the outcome and GCI reproducibility. For each study we report: the mouse strain and age used, the pre-operative procedure (fasting), 4 different approaches to the surgical procedure (choise of anesthetics, occlusion time and arteries occluded, if hypotension is induced, maintenance of body and scalp temperature), the post-operative procedure (post-surgery recovery), exclusion criteria, mortality, region specific delayed neuronal cell death and if any neurological tests were performed on the mice post-operatively. This table clearly illustrate the variability in how GCI is induced in mice. Abbreviations: Bilateral common carotid artery occlusion (BCCAo), global cerebral ischemia (GCI).

Study Mouse Fast- Anesthesia Arteries oc- Hypoten- Temperature of Post-surgery Exclusion Mortality Delayed Neurological test strain ing cluded and sion body and scalp recovery criteria neuronal cell and and age occlusion during surgery death Comments time 1 Male - 2.5% Bilateral - Rectal probe Artificially CBF <10% - Day 4 - - (Olsson et C57BL/ halothane in common ca- coupled to ventilated 10-30 within 1 sporadic cell 0.01 mg of the muscle re-

al. 2004) 6 70% N2O rotid arteries homeothermic minutes after minute after death 10-50% laxant drug norcuron was 31 or 10 and 30% O2 occlusion blanket surgery – then occlusion of CA1, CA2, given prior to GCI.

weeks (discontin- (BCCAo) Clamping tempor- extubated 90 both hemi- cortex and pCO2 concentration meas- ued 2 12 minutes al muscle minutes after pheres (de- striatum ured with capnometer minutes be- Continuous flow GCI induction. termined by from expired air in order fore end of warm humidi- Heating cabinet optical fila- to adjust ventilation to en- ischemia) fied air  com- for 24 hours at ments at- sure physiological blood bined keeps the 33.5oC tached to gasses. brain normo- Check rectal the skull thermic temperature 4 bone) times the first 24 hours 2 Male Overn 3% BCCAo Right jug- Pericranial needle Intubated and - - Day 3: Total motor score un- (Sheng et C57BL/ ight halothane – 10 minutes ular vein: thermometer artificially vent- CA1 total cell changed day 3 from nor- al. 1999a) 6 8-10 1.2% during With- ilated. death = 37% ± mal mice weeks operation drawal of Recover in oxy- 33%. Sporadic Mechanical 0.5-0.6 gen enriched en- cell death in ventilated – mL blood. vironment neocortex and tidal volume MABP = striatum 0.7 mL 30 mmHg during BCCAo 3 Male - 3% BCCAo - Rectal temperat- When declamp- When the 20 Day 5: 12 and - (Jeffs et C57BL/ halothane in 12, 15, 17 and ure (they claim ing CCA they isoelectric minutes 15 minutes of

al. 2008) 6NHsd 60% N2O 20 minutes this reflects the were inspected EEG is flat BCCAo – ischemia  6-8 and 40% O2. temperature of the for patency. the mice ex- mortality no significant weeks 1% during brain well) Artificially cluded of 100% neuronal loss, operation. Heat pad ventilated until within 24 17 minutes  Mechanical Heating fan they regain hour 80% of CA1 ventilated – spontaneous (n=5) neurons die tidal volume respiration. and 40% of 0.2 mL Recovery room CA2 neurons 30oC 6 hours die after GCI with regular temperature assess- ments 4 Male Overn 5% isoflur- BCCAo Isoflurane Pericranial needle Aritificially - - Day 3 and 5: No difference in total mo- (Onken et C57BL/ ight ane 10 minutes induced thermometer ventilated Re- 60% of the tor score between sham al. 2012) 6 70% N2O hypoten- Heating pad covery chamber neurons in and GCI mice o 10-11 and 30% O2 sion. Heating lamp 36-37 C the first CA1 die, Open field test show de- weeks 1.5% during MABP 24 hours sporadic cell creased total distance trav- operation = 40 death in stri- elled by GCI mice com- mmHg atum and cor- pared to sham. during tex Disadvantage: isoflurane is BCCAo neuroprotective 5 Male - 1-5% BCCAo Show Rectal probe Recovery for 24 They check Mortality Day 7: 50% of - (Wei et al. C57BL/ halothane 12 minutes MABP Scalp temperature hours in heat that CFB 30-40% at hippocampal 2008) 6 22- (optimal and don’t fall ensured by sub- chamber 33- decreases day 7 CA1 neurons 29g most reprodu- during dermal probe in 34oC, which during BC- die cible effects ischemia parietal bone re- maintained core CAo in each with this time, gion. body tem at hemisphere however, oth- Heat pad and heat 37oC (data not with laser er time points lamp shown). Doppler not shown) Artificially probes ventilated 6 Male - 5% Isoflur- BCCAo rely on Rectal 3 hours after - - Day 3: HE - (Webster C57BL/ ane mixed 12 minutes missing GCI in heat in- staining, et al. 6 with medic- posterior cubator at 37oC ~80% cell 2009) 8-12 al air and commu- death in hip- weeks oxygen de- nicating pocampus livered with artery – facemask. high mor- 2-3% during tality with operation. jugular catheter

7 Male - 4% isoflur- BCCAo - Rectal probe Heating blanket rCBF < Day 3: 30 Day 3: TUN- - (Yoshioka C57BL/ ane, in- 10, 15, 22 and Heating pad for 24 hours 13% - only minutes of EL positive Seizures observed in 5% et al. 6 traper- 30 minutes Heating lamp 0.5 mL acetated happens in BCCAo = cells in stri- of BCCAo for 22 minutes 2011) 8-12 ito-neal in- Anesthesia ringers solution mice 50%, 22 atum, CA1 and 18% of BCCAo for 30 weeks jection of turned off im- subcutaneously without pos- minutes of hippocampal minutes xylazine mediately 30 minutes and terior com- BCCAo region, cortex, Mild injuries with 15 after occlu- 24 hours after municating =18%, 15 dentate gyrus minutes of BCCAo, severe Facemask sion ischemia artery. minutes of injuries with 22 minutes of 70% N2O Briefly re-an- Inspect CCA BCCAo BCCAo

and 30% O2 esthesied with patency after =11% Chose 22 minutes as op- 1.5% iso- 1% isoflurane BCCAo timal ischemia period flurane dur- at reperfusion ing operation 8 Male - 3-1.5% iso- BCCAo - Rectal probe 3 hours at 30oC CBF < 15% - Day 3: - (Hong et C57BL/ flurane in 20 minutes Heating pad during first TUNEL posit- al. 2012) 6 70% N2O minute of ive cells in

23-27 g and 30% O2 occlusion hippocampal (measured regions CA1 with laser and CA2 Doppler flowmetry) 9 Laca - Chloral hy- BCCAo - Rectal probe After occlusion During BC- - Day 4 : signi- - (Gaur and strain drate i.p. Occlusion for arteries were in- CAo: main- ficant oxidat- Experiments performed Kumar 25-30g 360mg/kg 5 minutes, 10 spected patency tenance of ive damage between 9-15 in order to 2010) Housed minutes of dilated pu- (seen by in- minimize the circadian in reperfusion pils, ab- crease of ni- changes and inter-group groups and then 5 sence of a trite concen- variations of 2 24 minutes of oc- cornea re- tration, super- hours of clusion flex when oxidedis- accli- exposed to mutase, matiza- light, main- catalase, tion tenance of redox ratio) rectal tem- and mitochon- perature. drial en-zyme Animals dysfunc-tion having seizures where ex- cluded 10 Swiss - Chloral hy- BBCAo - Heating pad Recover indi- CBF must - Day 1: 17 Day 1: decreased memory (Rehni et albino drate i.p. 15 and 17 vidually be < 60- minutes 1% after GCI compared to al. 2010) of either 400mg/kg minutes overnight 70% in both TTC stain  sham( evaluation with el- sex 23- OR hemispheres 40% infarct evated plus maze test), de- 27 g Recovery in creased motor score after 33oC incubator GCI compared to sham with 50% hu- (rota rod test). midity 11 C57BL/ - Ketamine BCCAo - Rectal probe Kept on heating Mice that - Day 1: Young - (Zheng et 6 cocktail i.p.: 10 minutes Heating pad pad till they died within mice  30% al. 2010a) (young 50% ketam- young animals wake up less than 24 of cortical and males ine, 25% 5 minutes old hours of 12% of CA1 100 xylazine, animals (due reperfusion neurons die. days) or 10% acepro- to high mor- were ex- Old mice  Balb/c mazine, tality) cluded 25% of cortic- (old fe- 15% saline al and 10% of males CA1 neurons 450 die days) 12 (Fate- Male - 3% isoflur- BCCAo - - Recovery in - Saline Day 1-14: 1% Limb grasping and fore- hi-Has- CD1 ane in oxy- 45 minutes warm environ- treated an- TTC staining limb placing in cylinder sanabad >22g gen, admin- ment 1 h and imals –  20 % of test was decreased 1-14 and Task- istered nas- housed indi- significant hole brain days after GCI. No differ- er 2011) ally. 1% iso- vidually number dies, damage ence in motot score flurane dur- died. No in different between sham and GCI ing opera- overall brain regions mice with rota rod test. tion mortality Seizures seen in 14% of is given animals 13 Don’t Overn Chloral hy- BCCAo - Rectal probe Recovery in - - Day 3: neur- - (Wang et know ight drate 20 minutes Heating pad warm incubator onal cell death al. 2011) WT 400mg/kg 32-33oC CA1, CA3 strain and dentate gyrus 14 Male - Isoflurane BCCAo - Rectal probe - CBF must - Day 3: TUN- - (Cui et al. C57BL/ via 30 minutes Heating pad be < 20% EL positive Indicative signs of foreb- 2010) 6 facemask within the neurons in rain ischemia: unrespons- 20-25 g first minute hippocampus iveness, catatonic postures, 8-10 (60%), cereb- dilation of pupils and loss weeks ral cortex of righting reflex (40%) and 40 minutes of BCCAo  striatum many mice die (100%)

15 Male - 2% BCCAo - Rectal probe Recovery – tem- CBF must - Day 7: Nissl - (Kamide C57BL/ halothane 15 minutes Heating pad perature main- be < 15% staining  et al. 6 8-12 Maintained Heating lamp tenance until within first 30-40% of the 2012) weeks with 0.5% mice were alert minute of CA1 neurons with again occlusion have died facemask 16 Male - 2% BCCAo MABP in- Scalp thermomet- Recovery for 2 CBF must - Day 7: hippo- - (Kit- C57BL/ halothane 5, 10 and 15 creased er with diameter hours at 35oC in be < 10% campus and MAPB and blood gases agawa et 6 8-16 0.5% minutes traniently of 3 mm, attached a heating cham- within first caudoputamen seems to be measured in al. 1999) weeks halothane after BC- to skull over pari- ber minute of - survival mice during oper- CAo, etal cortex occlusion 5 minutes BC- ation with MABP Rectal probe CAo  no open decreased Heating lamp damage facemask after re- 10 minutes moval of BCCAo  5 BCCAo out of 12 mice ceel death 15 minutes  11 out of 12 mice cell death 17 Male - Sodium BCCAo - Rectal probe - - During Day 7: neur- Behavioral assessment by (Otsuka et C57BL/ pentobarbit- 10 minutes operation: onal loss in observing consciousness, al. 2009) 6 al 50mg/kg (Loose ligat- 51% mor- hippocampus, circling, torsion of neck 8 weeks i.p. ure around ca- tality no loss in and seizure – the mice that rotids, (50% have dentate gyrus died got a higher score wounds seizures). than mice that survived. closed and 20 20% of h later BC- the mice CAo for 10 that sur- minutes under vive have conscious seizures conditions) 18 Male Overn 3% BCCAo Right jug- Needle thermo- 15 μL 8.4% - - Day 3 and 5: Total motor score was not

(Sheng et C57BL/ ight halothane, 10 or 12 ular vein meter placed adja- NaHCO3 given 10 minutes different between GCI and al. 1999b) BJ 1.5% minutes cannu- cent to skull i.v. just after BCCAo  sham operated mice day 1, halothane (halothane lated to BCCAo 40% CA1 3 and 5 after the operation during oper- discontinued withdraw Artificially damage, ation. during BC- blood ventilated 10 minutes Ventilation: CAo) (0.5-0.6 Recovery in BCCAo + hy- 130 breaths mL) and oxygen enriched perglycemia per minute intra-ar- environment  75% CA1 terial infu- damage sion of 0.3 12 minutes mg tri- BCCAo  meth- 70-80% CA1 a-phan damage camsylate Neuronal cell  com- death in bined caudoputamen causes hy- and cortex as- potension. well 19 Male - Sodium BCCAo Blood Rectal probe Recovery cage - - - - (Zheng et C57BL/ pentobarbit- 20 minutes withdraw- Heating lamp at 25oC with 60- Cortical microvascular en- al. 2010b) 6 12 al: 50 mg/kg al (0.5 70% humidity dothelial cells  serious weeks mL) edema, basal lamina and through a mitochondria break down tail-artery GCI day 1  increased catheter expression of MMP-9 and phosphorylation of ERK1/2 20 Male - Isoflurane BCCAo - Rectal probe Artificially CBF must Day ?: Day 7: 60% of - (Zhen and CD1 5-6 5%, during 12-40 minutes Subcutaneous ventilated be < 10 % Sham = the CA1 hip- 15 minutes BCCAo  Dore weeks operation needle thermo- Heating cham- during first 0%, 12 pocampal 9/20 mice had asymmet- 2007) 2% isoflur- meter adjacent to ber 33oC for 48 2.5 minutes minutes neurons were rical hippocampal damage ane skull hours of BCCAo, BCCAo = dead due to different develop- Heating pad and inspect re- 11%, 15 ment of circle of willis in lamp covery of minutes mice  82% of mice had CBF 15 BCCAo = at least one hemisphere minutes 25, 20 without PcomA after BC- minutes = CAo 80% 21 Male All 3% isoflur- BCCAo Catheter Needle thermo- Artificially - - Day 3: 50% of Total motor score un- (Homi et C57BL/ mice ane in a 10, 15, 20 in right meter under right ventilated, tidal CA1 and CA3 changed after GCI com- al. 2003) J fasted mixture of minutes jugular temporalis muscle volume 0.5mL neurons died pared to sham with isoflur- 8-10 for 50% O2 and vein and Rectal probe To counteract in isoflurane ane anaesthesia but de-

weeks ˃12 50% N2O, 0.6-0.9 Heating lamp systemic acidos- anesthetized creased with fentanyl/N2O. hours during oper- mL blood is 8.4% NaH- GCI mice, Explain how isoflurane is

ation 1.2% withdrawn CO3 given i.v. 70% of CA1 neuroprotective  reduc- isoflurane  MABP Recovery cham- and CA3 tion in cerebral metabolic

OR = 35mm- ber with humid- neurons die in rate for O2 consumption, fentanyl Hg com- ified oxygen en- fentanyl/N2O protect against increased (25μg/kg*h) bined with riched environ- anesthetized catecholamine conc in in 70% N2O BCCAo ment GCI mice blood and its damaging ef-

and 30% O2 for 10 fects. BCCAo + hypoten- minutes sion  greater concentra- only tion of noradrenalin during GCI  systemically more stressful than BCCAo alone! 22 Male - 2% BCCAo - Metal plate ther- - CBF must - 2 hours after - (Yang et C57BL/ halothane, 12 minutes mometer inserted be < 10% of GCI: 80% of Rats and gerbils  CA1 al. 2000) 6 8-16 during oper- over cerebral cor- baseline CA4, 50% of region most vulnerable re- weeks ation 0.5% tex for scalp tem- during the CA2, 30% of gion to ischemic insult in halothane in perature first minute CA1 neurons brain. In mice  CA4, not open face Rectal probe – after BC- die lateral segment of CA1 mask measure until 2 CAo hours after GCI 23 Male - Chloral hy- BCCAo - Rectal probe Artificially - During Day 1 and 3: - (Murakam CD1 drate 350 3, 5 or 10 Heating pad and ventilated, tidal operation: injury in stri- Chloral hydrate induces i et al. 3 mg/kg and minutes blanket volume = High mor- atum, cortex slight hypotension com- 1998) months xylazine 4 0.5mL, 120 tality rate and hippo- pared to inhalation anes- 35-40 g mg/kg breaths per in 10 campus, cor- thesia since chloral hy- given i.p. minute minutes tical injury in drate inhibits respiration

Tracheal Recover in air BCCAo borderzone  high PaCO2 and low tube for conditioned group if between ACA PaO2 controlled room at 20oC mice were and MCA Hippocampal, striatal and ventilation not mech- cortical injury increase anically with ischemia time ventilated 24 Male Overn 3% BCCAo One group Needle thermo- Artificially Cerebral Day 1: Day 3: CA1 Total motor score day 3 (Wellons, C57BL/ ight halothane in 10, 15 and 20 where meter for scalp ventilated, tidal vasculature 100% sector of hip- was unchanged in GCI

III et al. 6 and O2, during minutes blood was temperature volume is anatomy with 15 pocampus  mice compared to sham- 2000) SV129 operation 1- withdrawn 0.7mL, 120 evaluated minutes of 30-40% dam- operated mice with 10 8-10 1.5% from cath- breaths per with indi- BCCAo aged in minutes of BCCAo weeks halothane in eter in minute a-ink  total C57BL/6 with C57BL/6 BCCAo with hy-

(this 50% O2 and right jugu- 15 μL 8.4% motor 10 minutes of potension  10 and 15 study 50% N2. lar vein to NaHCO3 given score de- BCCAo and minutes is the most effect- com- Halothane obtain in arterial cath- creased in hypotension, ive model found in this pares 0.5% during MABP = eter before re- these mice very little study. the 2 BCCAo 30mmHg moval day 1 damage in strains) during Recovery cham- compared SV129 BBCAo ber with 50% to sham. FiO2 for 1 hour 25 SV-129 - 2% BCCAo - Rectal probe and If one wild type - Seizures Day 3: neur- - (Fujii et and halothane, 30 and 75 scalp thermometer strain (parent to in 13% of onal cell death Halothane anesthezied: al. 1997) C57BL/ during oper- minutes (needle probe in transgenic mice) SV-129 in hippocam- C57BL/6 ischemic damage 6 males ation 1% (anesthesia temporal muscle). differs from the after 75 pal CA1, stri- following 30 minutes BC- 18-24 g halothane in turned off dur- Heating lamp and mutant then it minutes of atum and CAo = ischemic damage in (this 70% N2O ing BCCAo pad becomes essen- BCCAo cerebral cor- SV-129 with BCCAo for

study and 30% O2 and animals tial to develop (here 25% tex 75 minutes com- assessed for and test wild of the Chloral hydrate anesthesia: pares level of con- type littermates mice die SV-129 more resistant to the 2 ciousness  aswell) ischemic injury than strains) reanesthesized and in C57BL/6, ischemic injury before reper- 43% of greater in chloral hydrate fusion) C57BL/6 anesthesia than halothane after 30 since chloral hydrate minutes lowers MABP and CBF BCCAo Suceptibility to ischemic (here 0% damage between the 2 dif- of the ferent strains were not ex- mice died) plained by sensitivity of pial or other vessels to specific anesthetics  seen with cranial window technique RECOMMEND C57BL/6 26 Male - Light ether BCCAo - Rectal and scalp Observed at - 100% for 1-24 hours: - (Yang et C57BL/ anesthesia 20 minutes temperature room temp for C57BL/6 C57BL/6  All C57BL/6 died within 6 al. 1997) 6 in open face 24 hours at 6 hours, highly repro- hours of global ischemia ICR, mask. 80% for ducible  but showed most con- BALB/c Balb/c at ischemic dam- sistent neurological sign , 24 hours, age in hippo- during occlusion due to CBA, 60% for campus and missing PcomA seen with DBA/2, CH3 and caudoputa- indian ink perfusion and CH3 CBA at 24 men, ex- largest drop in CBF and ddY hours, amined after All mice of ddY and 8-16 20% for they died DBA/2 survived for 24 weeks DDY at hours (this 24 hours Almost all BALB/c and study ICR died within 24 hours com- of BCCAo pares the 7 RECOMMEND C57BL/6 strains)

27 (Bar- Male - Isoflurane CCAo or BC- - - - - Day 5: Day 7: - one et al. BDF, with open CAo BALB/c: 30 minutes of Similar hemodynamics in 1993) CFW facemask 10 and 30 15% with BCCAo  all strains and minutes 10 and 30 30-40% neur- BALB/c minutes of ons die in 22-32 g BCCAo, CA1 RECOMMEND BALB/c (this 60% with study 60 com- minutes of pares BCCAo the 3 strains)

28 Male - Isoflurane BCCAo with - - Artificially ven- CBF must 5% day 2 Day 1, 2 and - (Hua et C57BL/ 5%, during occlusion of tilated, tidal vol- be < 10% and 5% 3: neuronal al. 2006) 10ScSn operation left subclavian ume 0.5 mL, (laser dop- day 3 cell death hip- 25-30 g 1.5% iso- artery and 110 breaths per pler flow- pocampal flurane in right subclavi- minute metry) CA1, dentate 100% O2 an artery sten- gyrus, parietal Isoflurane osis cortex  turned of 12 minutes similar dam- during oc- age all days clusion of the carotid arteries 29 Male - Halothane, BCCAo com- - Rectal probe - - - Day 1, 4 and - (Yonekura C57BL/ during oper- bined with oc- Sclap with needle 28: 80% of et al. 6 and ation 1.5% clusion of microprobe (MT- CA1 neurons 2004) 129/Sv in 30% O2 basilar artery 26/2, physitemp die with 14 8-12 and 70% 8 and 14 instruments, minutes of weeks N2O in open minutes Clifton, US) BCCAo in face mask Heating blanket C57BL/6 30 Male - 3% BCCAo - Rectal probe 0.5 mL sterile - - Day 3: Mor- - (Kelly et MF1 halothane, 10, 15 and 20 saline after op- phologically Pilot study  max neuronal. 2001) (often during oper- minutes eration and abnormal al damage 3 days post BC- used in ation 1.2- ventilated neurons ex- CAo repro- 1.7% in (facemask) with hibit features MF1 mice significantly

ductive 70% N2O 100% O2 until of ischemic higher MABP during and de- and 30% O2 recovery from damage in ischemia than C57BL/6, velop- anesthesia hippocampus neuronal damage low in mental Recovery cham- and dentate MF1 and high in C57BL/6 biology) ber for 2 hours gyrus due to PcomA develop- and at 29oC ment C57BL/ 6 30-40 g 31 Male - 2% isoflur- BCCAo - Rectal and scalp CCA reflow in- Mortality Day 3: 40% of - (Tsuchiya SV129 ane, during 20minutes thermometer spected under rates (day 3) CA1 and 60% Initially BCCAo combined et al. and operation microscope = 25, 50, 75 of CA2 hippo- with hypotension  ex- 2002) C57BL/ 1.5% in Maintain tem at and 100% at campal neur- cluded due to high mortal- o 6 30% O2 and 25 C for 2 hours 15, 20, 25 ons die after ity technical difficulty

24-28 g 70% N2O postsurgery + and 30 20 minutes of variability in histological with face animals ob- minutes of BCCAo outcome mask served BCCAo RECOMMEND C57BL/6

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