Rat Models Flashcards
Metabolic disease
insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, obesity, and hypertension
Obesity
- Zucker Diabetic Fatty
- Spontaneously hypertensive obese rat (SHROB)
- Dietary induced obesity prone rat (DIO)
• Zucker Diabetic Fatty: leptin (recessive) mutation
o Outbred most widely used
• Hyperlipidemia, hypercholesterolemia, hyperinsulinemia
• Doesn’t usually develop Type 2 diabetes
• Spontaneously hypertensive obese rat (SHROB)
o SHR and Sprague Dawley cross
o Hypertriglyceridemia, spontaneous hypertension, hyperinsulinemia, hyperlipidemia
o Absence of leptin receptor leads to obesity
• Dietary induced obesity prone rat (DIO)
o Must be fed high energy/ fat diet
o Model of human obesity, non leptin deficient obesity
Diabetes
Diabetes, Type 1
o BBDP (inbred albino Biomedical Research Models) • Model of spontabeous autoimmune diabetes
Diabetes, Type 2
o Zucker diabetic fatty (inbred, hooded black and white)
• Primary model for Type 2 and effects on wound healing, periodontal disease, and neuropathy
• Females develop diabetes only on a different diet than do males
o Cohen diabetic rat and Goto Kakizaki (GK) rat
• Not obese
o Otsuka Long Evans Tokushima Fatty Rat
• Late onset of hyperglycemia with dev of Type 2 at 18 weeks of age then around 40 weeks of age Type 1 develops
• Chemically induced diabetes
o Streptozotocin: causes Type 1 by destroying pancreatic beta cells in adults and Type 2 in neonates
Hypertension
• Spontaneous hypertensive rat (SHR, albino, inbred)
o Insulin resistant as well
o WKY is used as control
• Genetically hypertensive rat (GH)
o Model of spontaneous hypertension
• Fawn hooded hypertensive rat (FHH)
o Spontaneous mutation of a Long Evans rat
o Renal damage in SHR
o All fawn hooded strains have hereditary bleeding disorder due to platelet pool deficiency
• Salt sensitive hypertension (Dahl-SS)
o SR/Jr is resistant
o High salt diet for 3-4 wks leads to hypertension and marked vascular and renal lesions
• Surgically induced renovascular hypertension- calmps of renal arteries
Epilepsy
• Genetically Epilepsy Prone Rats (GEPR/3 and GEPR/9)
o Dev from outbred Sprague Dawley by selecting for susceptibility to audiogenic induced seizures
• WAG/Rjj Rat (inbred, albino)
o Absence epilepsy
• Genetic absence epilepsy rat from Strasboug (GAERS)
o Generalized, nonconvulsive epileptic seizures
Multiple Sclerosis
• Experimental autoimmune encephalomyelitis: demyelinating lesions in the CNS from a Th1 inflammatory response o Lewis (LEW) and Dark Agouti (DA) o Induced with myelin basic protein +/- incomplete Freund’s adjuvant
Parkinson’s Disease
- Dopamine depletion through administration of 6-hydroxydopamine bilaterally into the nucleus accumbens septi
- Langston model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- Rotenone administration
Cancer
• Prostate cancer: Lobund Wistar Rat (LW)
o Spontaneous or induced with N-methyl-N-nitrosourea/ testosterone
o Noble Rat
• Mammary cancer: Copenhagan, Wistar Furth
Rheumatoid arthritis
• Chronic autoimmune disease with inflammation of joint linings and=/or other internal organs
• Models
o Collagen induced arthritis model
• Complete or incomplete Freund’s adjuvant or pristine
• Develop autoimmune mediated polyarthritis
• LEW and DA commonly used
o Adjuvant induced arthritis model
Menopause: cessation of ovarian cyclicity resulting from depletion of ovarian follicles by atresia
• Primordial follicles are a finite pool of oocytes arrested in meiosis
o Progress from primordial to ovulatory stages after puberty
o Most follicles undergo cell death by atresia
o Pool of primordial follicles becomes depleted and ovarian failure (menopause) occurs
• Surgical ovariectomy dot not mimic natural menopause as ovarian steroid hormone production is altered
o Androgens still produced by ovary post menopause
o Just stops producing estradiol
• IP 4-vinycyclohexene works in mice and IP 4-vinyl-1-cyclohexene diepoxide works in mice/ rats
Rheumatoid arthritis
Aortic banding (pressure overload) model of heart failure
- Band ascending and descending aorta in rats to produce severe ventricular hypertrophy after about 12 weeks
- Mimics stenosis of the aortic valve
Stroke
• SHR A1 and A3 substrains: model of hypertension and cerebrovascular disease
• Spontaneous hypertensive heart failure rat (SHHF)
o Model of obesity, Type 2 diabetes, and congestive heart failure
• Surgical myocardial infarction: ligate left anterior descending coronary artery
• End stage renal disease associated with hypertension, diabetes, and polycystic kidney disease
o Diabetes and hypertension results in an increase in glomerular filtration rate, proteinuria, and glomerular lesions
o Renal disease associated with metabolic syndrome (hypoinsulinemia, hyperinsulinemia, impaired glucose tolerance)
o ZSF1 rat
diabetic nephropathy
o Hypertension and diabetes on renal function
ZDF, SHORB, SHR, SHRSP, Fawn hooded, GH, and Dahl SS/J
• Polycystic kidney disease (Bright’s disease)
o Han: SPRD (Han: Sprague Dawley (Cy/+) rat
• Diabetes Insipidus: neurogenic deficiency of antidiuretic hormone or insensitivity to the antidiuretic hormone
o Kidney does not reabsorb proper amount of water
o Brattleboro rat: neurogenic form (hypothalamus dysfunction)
FANFT- N-[4-(5-Nitro-2-furyl)-2-thiazolyl] formamide: induces 100% incidence of
bladder carcinoma
Coopenhagen (COP) Rat: Strain carries dominant resistance gene
mammary cancer
Wistar-Furth (WF) Rat: Susceptible to inducible carcinomas.
mammary cancer
Chemically induced via dimethylbenzanthrecene (DMBA)*
mammary cancer
Lobund-Wistar (LW):
only rat strain genetically predisposed to spontaneous metastasizing, sex hormone- influenced adenocarcinoma*. prostate
2 ways to develop model in LW rats Lobund Wistar prostate adenocarcinoma
1) Spontaneous (takes 26 months) or 2) ENU + testosterone* (take 10.5 months). The latter stage “premalignant/chem induced” is susceptible to intervention, but late-onset spontaneous is not
Noble Rat*:
Inbred, black hooded. Chemically induced with testosterone and 17-B-estradiol capsules implanted capsules for 16 wks→ hyperplasia of DL prostate. Longer exposures→ 100% get prostatic carcinomas
4-vinycyclohexene
chemically induced menopause (destroys ovarian follicles) in mouse ONLY
vinyl-1-cyclohexene diepoxide (VCD)
chemically induced menopause (destroys ovarian follicles) in rats AND mice
rheumatoid arthritis Type II collagen-induced:**
DA (Dark Agouti) and BB (DR)/Wor = very susceptible LEW = not susceptible
rheumatoid arthritis, adjuvant induced
CFA or ICF, pristane, streptococcal cell wall extracts. LEW – very susceptible to streptococcal wall isolates
Surgically Induced Myocardial Infarction in Rats:**:
ligation of the LAD (left anterior descending) coronary artery
Works because rat doesn’t have a large left circumflex branch*, but difficult to predict when CHF will occur. Almost 100% rat model (vs. mice).
Spontaneous Hypertensive Heart Failure Rat
Model of obesity, Type II DM and CHF
Brattleboro Rat
This is an outbred, hooded rat model of hereditary hypothalamic diabetes insipidus→ demonstrates neurogenic characteristics. Main features: High plasma renin activity, high angiotensin II, spontaneous hypertension, abnormally large volume of dilute urine (d/t lack of vasopressin)
DBA/2 mice
:** Young mice are susceptible to audiogenic seizures which decreases as they reach adulthood
Dilute, brown, non-agouti
Parkinson’s Disease**
• Characterized by loss of ~50–70% of dopaminergic neurons in the substantia nigra pars compacta, loss of dopamine (DA) in the
striatum & presence of intracytoplasmic inclusions called Lewy bodies (LB), composed mainly of α-synuclein * & ubiquitin
Parkinson’s C/S
• Main features are motor manifestations (tremors, rigidity, bradykinesia, & postural instability) however, non-motor (olfactory deficits, sleep impairment & neuropsychiatric disorders) may also be present
o 6-OHDA
Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine
irrerversible Parkinson’s
o MPTP
1 methyl-4-phenyl- 1, 2, 3, 6- tetrahydropyridine
irreversible Parkinson’s
rodent Parkinson’s
) Mouse or Rat: Induction with 6-OHDA or rotenone. See classic brain pathology and motor phenotype.
Note: Minimal disease in rodents using MPTP (1 methyl-4-phenyl- 1, 2, 3, 6- tetrahydropyridine aka Langston model). This is in contrast to NHPs (OW NHPs more sensitive than NW, older more sensitive than younger!!) Read chapter NHP BB Vol II Ch 15.*
Spontaneous Hypertensive Rat (SHR)**
- Developed from WKY outbred (female with severe hypertension x male with mild)→ bred for high BP w/o diet or environ stimuli
- Most popular rat hypertension model*
- Polygenic (at least 3 genes responsible for high BP). BP ~ 150 mmHG at 10 wks.
- Some SHR sub-lines are also stroke prone
- Excellent for screening anti-hypertension drugs
- Insulin resistant
- WKY rat is considered a SHR control*, but is only 50% homologous; other normotensive strains might be equally appropriate
Non-Obese Diabetic (NOD) Mouse**
- Best mouse model of spontaneous autoimmune insulin dependent Type I DM
- Analogous to BBDP/Wor (Bio-Breeding (BB) Diabetic Prone) Rat
) Otsuka Long Evans Tokushima Fatty (OLETF) Rat*
• Model of Type I DM (pancreatic islets destroyed at wk 40)
Goldblatt kidney
o Two kidney, one clamp model = Goldblatt kidney
• High rennin model of hypertension
