Toxic Effects of Neotyphodium Coenophialum in Cattle and Horses

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UTILIZATION, QUALITY AND ANTI-QUALITY FACTORS

- 17 -
Toxic Effects of Neotyphodium coenophialum in Horses

Dee L. Cross

ABSTRACT

Tall fescue (Lolium arundianceum) infected with the endophytic fungus Neotyphodium

coenophialum (E+) negatively affects herbivores that consume it. Horses (Equus caballus) are

more sensitive to the alkaloids in E+ tall fescue than cattle (Bos spp.) and exhibit increased

gestation lengths, dystocia (birthing difficulty) with an increased rate of foal and mare mortality,

and thickened placentas that have a tendency to separate prematurely (referred to as red-bagging),

with a high rate of stillborn foals. Mares that have grazed E+ tall fescue also have poor milk

production and a high rate of agalactia (lack of lactation). Sometimes, agalactic mares are

aggressive towards their foals. Mares that have ingested E+ tall fescue tend to have lower IgG

levels than normal, and it appears that their foals do not absorb the available IgGs as well as

normal foals. Foals born to mares eating E+ fescue tend to be less vigorous for 2 to 3 wk post-

foaling and some exhibit “dummy-like” behavior at birth. Growth rate of such yearlings is lower

than normal unless they receive supplemental feed. Preliminary research data suggest that mares

on E+ fescue have prolonged luteal (corpus luteum, located on the ovary) function, decreased per

cycle pregnancy rates, and increased early embryonic death rates. Oral administration of

domperidone 10 to 20 d prior to expected foaling effectively prevents the signs of fescue

toxicosis in gravid mares. Domperidone administered to 1,423 mares in the United States under
veterinarian supervision and under field conditions was 95% effective in preventing signs of tall

fescue toxicosis.

Keywords: tall fescue, endophyte, domperidone, dystocia, agalactia, prolactin, placenta, ergot

alkaloids.

Abbreviations: ACTH, adrenocorticotrophic hormone; CRH, corticotrophic releasing hormone;

E-, endophyte free, free of Neotyphodium; E+, infected by wild Neotyphodium endophyte; HPA,

hypothalamic-pituitary-adrenal axis; NRC, National Research Council;

PRL, prolactin; TSH, thyroid stimulating hormone.

INTRODUCTION

During the Middle Ages, there were numerous incidences of human toxicosis involving

hallucinations, convulsions, delusions, and gangrene. The syndrome became known as “St.

Anthony‟s fire”. In some instances, people actually jumped from buildings during hallucinogenic

states. Barger (1931) determined that ergot alkaloids from the Claviceps purpurera fungus were

the causative agent. Ergot alkaloids (see Chapter 13, Alkaloids) are characterized by an indole

group, which is a component of a tetracyclic ring known as an ergoline ring (Lorenz, 1979). Most

of the sclerotia, containing the ergot bodies, can be removed during the grain cleaning process.

However, small amounts have been detected in a variety of grains destined for human

consumption (Scott et al., 1992). Therefore, even with modern grain processing methods, ergot

alkaloids pose some threat to the human population.

Interaction of ergot alkaloids with receptors

Ergot alkaloids exhibit a high affinity for -adrenoreceptors, D2 dopamine receptors, and

several subtypes of 5-HT receptors (Pertz and Eich, 1999). The various alkaloids may act as

2
receptor agonists or antagonists, depending on the receptor and the particular alkaloid.

Ergovaline was shown to activate 5-HT2A receptors and thus induce contractions of blood vessels

(Dyer, 1993). As a result, blood flow to the vascular beds was reduced. Further research by

Schoning et al. (2001) confirmed the interaction of ergovaline with 5_HTIB/ID, and -

adrenoreceptors. Many of the toxic effects of ergot alkaloids can be explained by changes in

vascular blood flow (see Chapter 12, Physiological Basis of Fescue Toxicosis), as proposed by

Cross (1997). Strickland et al. (1994) reported that ergovaline was a D2 dopamine receptor

agonist in rat pituitary cells. In that study, ergovaline blocked the release of prolactin by cultured

pituitary cells. The D2 dopamine receptor antagonist, domperidone, prevented the prolactin-

lowering effect of ergovaline. Therefore, the effects of ergot alkaloids in milk production and

agalactia probably can be explained by their effect on D2 dopamine receptors.

Effect of ergot alkaloids on the immune system

Immunologists generally agree that recent evidence suggests a balance between prolactin

(PRL) and glucocorticoids is important in regulating the immune response. Numerous studies

have reported a reduction in PRL levels when ergot alkaloids are consumed (reviewed by Cross

et al., 1995). Natural killer cell activity is suppressed by several dopamine receptor antagonists

(huxthine, fluphenazine, pimoicide, and aalopeudal, in a PRL-dependent manner (Fiserova and

Pospisil, 1999). They theorized an interaction between ergot alkaloids and lymphoid cells and

tumor cells based on indirect findings: (1) expression of dopamine, serotonin or -

adrenoreceptors or lymphocytes that can be involved in the action of ergopeptines; (2) inhibition

of signaling pathways through intracellular enzymes (serin/heronin kinases, Ras-MAPK), leading

to mitogenesis by activation of the adenylate cyclase system (D2 agonistic, PRL inhibitory

eeroglines); (3) interaction with the nuclear structures or direct binding with DNA, including

3
derivatives of agroclavine, festuclavine, and several ergopeptines (LSD, ergosine, ergosinine, and

dihydroergosine).

Toxicity of the ergot alkaloids of Neotyphodium coenophialum

Since the release of „Kentucky-31‟ tall fescue seed in 1942 (see Chapter 1, Origin and

History), the cultivar has been used widely by livestock producers and the turfgrass industry. It is

hardy in a wide range of soil types (see Chapter 3, Adaptation and Suitability Zones), persistent

under heavy traffic and overgrazing, and relatively drought and pest resistant (see Chapter 4,

Abiotic Stresses and Endophyte Effects, Chapter 8, Diseases and Endophytes, Chapter 9, Insect

Pests and Chapter 10, Nematodes) when compared to other pasture grasses (Siegel et al., 1984).

After its release, it was observed that cattle consuming the grass did not perform (see Chapter 16,

Neotyphodium Effects on Cattle) as well as the nutritional analysis of the forage (see Chapter 11,

Nutritive Value) indicated that they should have performed. Instead, tall fescue began to gain a

reputation for causing reproductive problems and poor pre- and post-weaning calf performance.

Cattle consuming tall fescue during hot summer months appeared to be more stressed than

normal and frequently stood in water or created mud wallows. Occasionally, lameness was

detected and in extreme cases a foot would become detached, especially after cold winter

weather. Horse owners also began to notice agalactia, prolonged gestations, foaling difficulties,

and sometimes mare and foal deaths due to dystocia in pregnant mares grazing tall fescue

pastures (Garrett et al., 1980).

Bacon et al. (1977) reported the first conclusive evidence of the presence of an

endophytic fungus in tall fescue that was later identified as Neotyphodium coenophialum (Glen

et al., 1996).

4
TOXICOSIS IN HORSES

For many years, veterinarians and horse owners reported reproductive problems in mares

that consumed tall fescue (Garrett et al., 1980; Villahoz et al., 1984; Poppenga et al., 1984).

Monroe et al. (1988) determined that the endophyte of tall fescue is the causative agent for

reproductive abnormalities in gravid mares (Fig. 17-1). They reported that increased gestation

lengths, agalactia, foal and mare mortality, tough and thickened placentas, weak and dysmature

(large-framed emaciated-looking) foals, and reduced serum prolactin and progestagen levels

occurred in mares consuming E+ pasture, whereas gravid mares on endophyte-free (E-) pasture

appeared normal.

125
*
100
*
75
*
Percent

E-
* E+
50

0
Gestation Stillborn Foals Agalactic Placental Mares Re bred
Length Mares Re tention

Figure 17-1. Comparison of the effects of E+ and E- tall fescues on gestation length, foal
mortality, agalactia, incidence of placental retention, and rebreeding response in mares
(adapted from Monroe et al., 1988). Stars indicate significant difference between
treatments (P<0.05).

5
Gravid mares

Increased length of gestation. Gestation length of mares increased 27 d when consuming E+

fescue, compared to mares consuming E- fescue (Monroe et al., 1988). Putnam et al. (1991),

Earle et al. (1990), and Redmond et al. (1994) observed similar results. Severe dystocia is

frequently observed in mares that try to foal after an extended gestation period. Supplementing E-

and E+ mares on pastures with 50% of their National Research Council (NRC) requirements for

energy, using whole shelled corn, provided no beneficial effects on length of gestation or

dystocia. In the Earle et al. (1990) study, 66% of the mares grazing E+ with energy

supplementation exhibited prolonged length of gestation and died due to dystocia, whereas the

same signs and effects were noted for 50% of the mares grazing E+ without supplementation.

Putnam et al. (1991) reported 10 of 11 mares grazing E+ fescue experienced obvious clinical

dystocia, and 4 of them died during parturition, with only one foal surviving the natal period.

The dystocia appears to be a result of inadequate preparation of the reproductive tract for

foaling, prolonged gestation and fetal malpresentation. Due to prolonged gestation, foals usually

have larger than normal skeletal frames, increasing the difficulty of expelling the fetus through an

unprepared tract (Monroe et al., 1988; Putnam et al., 1991; Redmond et al., 1991). Additionally,

foals are often rotated 90 to 180° from the normal position for delivery (Taylor et al., 1985;

Monroe et al., 1988; Redmond et al., 1994). The failure of events that initiate preparation for and

cause normal parturition results in the subsequent catastrophic events of dystocia, as well as, in

some instances, mare and foal mortality when mares graze E+ fescue.

Agalactia. The effects of endophyte consumption on milk production vary among species. Cattle

(Strahan et al., 1987; Porter and Thompson, 1992; Schmidt and Osborn, 1993, Irwin, 1994),

6
sheep (Ovis aries) (Stidham et al., 1982), and mice (Mus musculus) (Zavos et al., 1988, Siegel

and Bush, 1988) have been shown to have reduced milk yields, whereas horses (Monroe et al.,

1988; Fig. 17-1) and rabbits (Oryctolagus spp.) (Daniels et al., 1984) exhibit reduced milk yields

or complete agalactia. The connection between tall fescue toxicosis and lactogenesis (milk

synthesis) seems to be through the effects of the ergot alkaloids on lactogenic hormones. Cattle,

sheep, and mice have both placental lactogen and prolactin (Forsyth, 1986). In contrast, horses

and rabbits rely on prolactin to stimulate prepartum lactogenesis (Forsyth, 1986). The depressive

effects of the ergot alkaloids on prolactin secretion may suppress the effect of prolactin on

lactogenesis in cattle, sheep, and mice, but have little or no effect on placental lactogen, a

lactogenic hormone. Consequently, the placental lactogen and the small level of pituitary

prolactin, a hormone produced by the anterior pituitary, may be sufficient to initiate prepartum

(prior to parturition) lactogenesis in these species and allow lactation to begin after parturition. In

the horse, it seems that the reduced prolactin secretion from the pituitary lactotrophic cells results

in agalactia. The alkaloids in the tall fescue/fungal endophyte symbiont are serving as D2

dopamine receptor agonists at the pituitary level (Strickland et al., 1992). In addition, the horse,

unlike ruminant herbivores, does not benefit from pre-gastric metabolism of alkaloids and would

be subject to absorption of larger amounts of the alkaloids from E+ tall fescue (Wachenheim

et al., 1992).

Eighty-eight percent of mares were agalactic when maintained on E+ fescue up to foaling

(Monroe et al., 1988; Fig. 17-1). The milk of agalactic mares often appears as a brown or straw-

colored oily-looking fluid, rather than the white milk of normal mares. This fluid has little

nutritional value, and foals invariably die unless bottle-fed. Another frequent complication

7
affecting foal viability is the lack of normal immunoglobulins in foals from mares that have the

straw colored fluid rather than white milk (Kouba, 1995).

Placentas. The placentas of mares grazing E+ tall fescue are thickened, reddish colored, and

heavier with an increased rate of retention than for E- mares (Monroe et al., 1988). Frequently,

the foal is presented normally but encased in a tough, thickened chorioallantois (a membrane

surrounding the foal in the placenta) membrane, which it cannot break through; consequently, the

foal suffocates unless an attendant is present to cut the chorioallantois immediately. Using an

Ingstrom meter to measure stress and strain, these E+ placentas appeared to be more resistant to

forces that would tear them, partially explaining why some foals are unable to break through the

thickened placentas (Monroe et al., 1988). Taylor et al. (1985) reported heavier and thicker

placentas from many mares consuming E+ seed than from mares consuming E- seed; DNA,

RNA, and collagen content were greater in the placentas of mares consuming E+ seed.

Brendemuehl et al. (1994c) reported on mares that grazed E+ fescue either continuously, from

300 d of gestation to foaling, or from gestation day 60 to 300, or had no exposure to fescue. They

observed an increase in weight and width of combined chorioallantois from mares exposed to E+

fescue continuously or from day 300 to foaling. Brendemuehl (1994c) reported increased

placental thickness in E+ mares immediately before parturition. Using 12 E+ and 12 E- mares,

increased placental thickness was observed in 10 of the E+ mares a mean of 6.5 hr prior to the

onset of parturition, while another E+ mare demonstrated an increase in placental thickness 32 h

prior to parturition. An elective Cesarean section was performed in one E+ mare at 358 d of

gestation and within 2 h of noting an increase in placental thickening. At surgery, the placenta

was reported to be thickened in a plaque-like fashion in the ventral portion of the gravid horn, the

uterine horn that contains the fetus. The thickened portion of the chorioallantois was noted to be

8
separated from the uterus. Pre-mature placental separations are common during the last trimester

in mares grazing E+ fescue and are commonly referred to as red-bag. Frequently these mares

develop udders prematurely and may leak milk.

Foal vigor and viability. Monroe et al. (1988) observed large-framed, dysmature and emaciated

looking (poor muscle mass) foals with overgrown hooves from mares grazing E+ fescue that had

an average gestation length 27 d past the expected foaling date, when those foals survived the

birthing process (Fig. 17-1). These foals appeared weak and many times exhibited a “dummy-

like” behavior. Later, with proper care, the foals appeared normal (Monroe et al., 1988; Earle et

al., 1990). Septicemia (bacterial infection at or near birth) is a frequent problem and is likely a

result of the low level of passive immunity. Putnam et al. (1991) reported that of 11 mares

grazing E+ fescue, only three foals were alive at birth, and only one of the three survived the first

month of life. In that study, dysmaturity or neonatal death of foals was not observed in 11 mares

grazing E- pastures.

Taylor et al. (1985) and Kosanke et al. (1989) observed lack of lung maturation in

stillborn foals born to E+ mares. Amniotic fluid from E+ mares lacked pulmonary phospholipids,

and phosphatidylethanolamine was present in only 12% of those E+ mares (Clare et al., 1994).

These data suggest that lack of lung maturation may be a contributing factor to the high rate of

foal death observed from mares on E+ fescue. Boosinger et al. (1994) examined several organs

and tissues from foals of E+ and E- mares. Histologic studies of thyroid glands from foals

exposed to E+ continuously or after gestation day 300 revealed numerous distended colloid-filled

thyroid follicles lined by flattened cuboidal epithelial cells. Mean plasma T3 concentrations were

reduced in these foals. Foals from mares exposed to E+ continuously or from day 300 to foaling

9
demonstrated a response to thyroid stimulating hormone (TSH) by showing improved mental

alertness, desire to stand, and good suckle reflex.

Brendemuehl (1995) collected colostrum from normal mares and tested it for IgG

concentration. Foals from mares exposed to E+ fescue continuously or from gestation day 300

were administered 1L of the pooled, collected colostrum collections by nasogastric tube within

1 h of birth. Compared to control foals not from E+ or E- fescue mares, these foals had decreased

serum IgG concentrations. These data suggest that foals from E+ mares receive less IgGs from

the milk produced by the mares, and their absorption rate was lower even if the milk IgG levels

were at or near normal levels. These factors, combined with the lower level of colostrum

production in E+ mares, explain why many foals from E+ mares quickly become septic. The

lower colostrum and nutrient intake from milk, especially IgG, probably accounts for many foal

deaths from E+ mares that have live foals at birth. Brendemuehl et al. (1994a) observed lower

serum T3, ACTH, cortisol, and total progestogen levels in foals from E+ mares compared to foals

from E- mares.

Body temperature, blood flow and laminitis. In cattle and sheep, blood flow to the

peripheral tissues decreased and body temperature increased when tall fescue seed was included

in the diet (Rhodes et al., 1991). The reduction in blood flow to the peripheral tissues is probably

related to increased body temperature because the animal is less efficient in cooling itself. Unlike

cattle and sheep, pregnant mares exhibit no increase in body temperature when exposed to the

endophytic toxins (Monroe et al., 1988; Putnam et al., 1991). However, horses sweat more freely

than cattle and are more capable of cooling themselves. Putnam et al. (1991) observed increased

sweating in gravid mares grazing E+ tall fescue. In cattle, it seems that peripheral

vasoconstriction, i.e., reduction in size of the blood vessels, caused by the alkaloids of E+ tall

10
fescue results in “fescue foot” (see Chapter 18, Toxic Effects of Neotyphodium in Seed Straw)

(Solomons et al., 1989). Rohrback et al. (1995) reviewed data from 185,781 horses of which

5,536 had a diagnosis of laminitis. Although these data were preliminary, they concluded that

there appeared to be a relationship between laminitis in horses and consumption of E+ tall

fescue. Abney et al. (1993) observed a vasoconstrictive effect of ergot alkaloids on equine

vessels in vitro. Carbohydrate overload and aqueous extract of black walnut (Galey et al., 1990)

are associated with the development of laminitis in horses. The aqueous extract of black walnut

caused post capillary venoconstriction (reduction in size of the vein), increased capillary

hydrostatic pressure, and transvascular fluid movement (movement through the capillary wall),

resulting in increased tissue pressure, edema, vascular collapse, and ischemia (reduced blood

perfusion) in the equine digit (Eaton et al., 1995). It is possible that through interaction of the

ergot alkaloids with the adrenergic receptors of the sympathetic nervous system, similar

responses may be occurring in horses consuming E+ fescue. Direct evidence for this theory does

not exist.

Mare abortions and fertility. Abortions in mares occur after rapid separation of the placenta

from the endometrium, a layer of the uterus. Of 1,211 abortion/stillbirths presented to a

diagnostic laboratory in Kentucky, placentitis and dystocia were the commonly diagnosed causes

(about 11%, each), with congenital abnormalities (8%), twins (6%), umbilical cord torsion and

premature placental edema (4%, each) and Equine Herpes Virus and other bacterial infections

(3%, each) being the other diagnostic causes (Pugh and Chapman, 1996). Red-bag, or premature

placental separations, and stillborn foals, are frequently reported by veterinarians and horse

owners in the field for mares grazing E+ fescue.

11
Brendemuehl et al. (1994b) observed the effects of E+ fescue on mare cyclicity,

pregnancy rates and embryonic death rates. Mares grazing E+ pastures had prolonged luteal

functions, decreased per cycle pregnancy rates, and increased early embryonic death rates, when

compared to those grazing E- pastures.

Growing horses

Effects on growth rate and digestibility. Consumption of E+ tall fescue, or treatment with tall

fescue extract, caused a reduction in rate of gain and feed intake in cattle (Schmidt et al., 1982;

Hoveland et al., 1983; Bond and Bolt, 1986), rats (Rattus spp.) (Neal and Schmidt, 1985), and

rabbits (Daniels et al., 1984). No reduction in growth rate was observed in yearling horses when

corn-based concentrates were used to supplement E+ or E- hay (McCann et al., 1992).

Pendergraft and Arns (1993) observed similar gains in yearling horses consuming E+ or E- hay

with concentrate supplementation to meet NRC requirements for growth. However, average daily

gains were reduced by 57% (0.24 and 0.56 kg for high- and low-endophyte treatments,

respectively) in yearling horses grazing E+ pasture without supplementation, with a reduction in

gain similar to that observed for steers in the same study (Aiken et al., 1993).

Redmond et al. (1991) and McCann et al. (1992) observed lower intake and digestibility

for E+ hay fed to mature geldings and yearling horses, respectively. McCann et al. (1993) and

Pendergraft and Arns (1993) found no differences in digestibility due to the presence of the

endophyte in hay when yearling horses were fed concentrate with the hay. Concentrate

supplementation was used in both studies to meet NRC requirements for growth for yearling

horses.

These results suggest that the effects of endophyte consumption on digestibility and

growth rate may be lessened by the inclusion of concentrates in the diet. In contrast, energy

12
supplementation has no beneficial effects for alleviating lactation and reproductive problems in

gravid mares that graze E+ tall fescue pastures (Earle et al., 1990).

Performance horses

Vivrette et al. (2001) evaluated the effect of E+ fescue on cardiorespiratory and

thermoregulatory aspects of performance horses. Fourteen Quarter Horses grazed either E- or E+

tall fescue pastures. Subsequently, the horses were exercised at 4 m/s (9 mi/h), a brisk trot, for

0.5 h and a distance of 7.2 km (4.5 mi) over rolling terrain. Respiratory rates were higher in

horses grazing E+ pasture during the 3.5 h post-exercise period. In horses that had grazed E+

heart rates and skin temperatures remained above pre-exercise levels for 2.5 and 3.0 h,

respectively. In E- horses, heart rates and skin temperatures of horses from E- pastures returned

to pre-exercise level 1.5 h after exercise. Water consumption following exercise for E- and E+

horses was 21.2 and 35.9 L (5.6 and 9.5 gal), respectively. These data suggest a negative effect of

E+ fescue on performance when horses have been grazing E+ pasture immediately prior to

exercise.

MANAGEMENT AND TREATMENT OF N. COENOPHIALUM TOXICOSIS

Pasture management

Personal interviews of horse owners and veterinarians, and clinical research have revealed

that many horses exhibit most of the signs of tall fescue toxicosis while consuming even small

quantities in hay, small patches of E+ fescue in paddocks, or even by grazing a small quantity of

E+ fescue under paddock fences (Cross et al., 1999). Therefore, to prevent toxicosis in horses,

E+ tall fescue must be eliminated completely in pastures. Personal experience and interviews

with livestock owners throughout the United States attest to the extreme difficulty of eliminating

13
E+ fescue from pastures. Experience has shown that unless pastures are completely devoid of E+

plants and viable seed, the E+ plants begin to thrive and become significant problems within 1 to

3 yr after re-planting pastures. Best success with pasture re-seeding (see Chapter 5, Stand

Establishment and Renovation of Old Sods for Forage) has come through the use of chemical

destruction of the fescue or an intense fallow followed by aggressive choke crops (crops that

have a dense canopy) for 2 yr before reseeding to another pasture forage. Establishment of clover

or other forage mixes with E+ fescue seems to be a reasonable alternative for cattle (see Chapter

6, Management to Optimize Grazing Performance in the Northern Hemisphere and Chapter 7,

Management in New Zealand, Australia and South America), but not for horses.

Grazing behavior

The horse is a notoriously selective grazer and will choose many alternative forage

species before consuming E+ tall fescue. Under low grazing pressures, many mares will spot

graze other species of forage and never exhibit any signs of fescue toxicosis. Changes in grazing

pressure or lack of availability of alternative forages quickly can force E+ fescue consumption

and generate the classical signs of fescue toxicosis. This partially explains why some horse

owners appear to have little or no fescue toxicosis when a few mares are grazing a large acreage

of mostly E+ fescue, and other horse owners routinely have problems with mares grazing E+

fescue.

Removal of mares from E+ pastures

There is evidence to suggest that the effects of E+ fescue are greatly reduced if mares are

withdrawn from E+ pastures at least 30 to 40 d prior to the date of expected foaling (Taylor,

1993; Brendemuehl et al., 1994c). However, most veterinarians recommend removal of mares

14
from E+ pastures from 30 to 40 and up to 90 d prior to expected foaling. With this management

approach, red-bag and the other signs of fescue toxicosis are greatly minimized.

Therapeutic treatment

Dilution of toxin intake. Gravid mares were fed 50% of the NRC requirement for energy as

cracked corn for the last 90 d of gestation (Earle et al., 1990) while grazing an E+ fescue pasture.

The practice had little effect on eliminating the negative results of consuming E+ fescue. Foal

mortality was 66 and 100% for the energy and the no energy supplement treatments, respectively.

This study confirmed the severity of the problem under the typical grazing conditions found in

the southeastern United States.

Initiation of
5 Drug Therapy

4
Ma mmary Score

*
2
*
* *
1 *

0
-31 -24 -21 -14 -11 -4 -1 4 9 14
Days from Calculated Date of Parturition

1.1 mg/kg 1.65 mg/kg
2.2 mg/kg Endophyte-Free Control
Endophyte-Infected Control

15
obtained 1.2 d before initiation of drug treatment). Stars indicate first detectable
difference (P< .05) from pretreatment values within treatment. Numbers indicate number
of animals remaining in treatment group when sample was obtained (from Redmond,
1994).

Dopamine antagonists (receptor blockers). Strickland et al. (1992, 1994) studied the effects of

ergot and loline alkaloids of E+ tall fescue on prolactin release by isolated and perfused

(circulation of media through the cells) rat pituitary cells. The ergot alkaloids lowered prolactin

concentrations and mimicked dopamine action. The use of a D2 dopamine receptor antagonist

(domperidone) blocked the effect of the ergot alkaloids and prevented their prolactin lowering

effect. Domperidone is a D2 dopamine receptor blocker that does not cross the blood brain

barrier and elicit neuroleptic (central nervous system effects) side effects. Domperidone was

administered orally (1.1 mg/kg body weight) to gravid mares grazing E+ tall fescue (Redmond

et al., 1994). It resulted in an increase in serum prolactin and progestagens (progesterone and its

derivatives) and provided what seemed to be nearly complete recovery of gravid mares from tall

fescue toxicosis with no observed neuroleptic side effects. Treated mares produced milk, had live

and healthy foals, and their gestation length was similar to the calculated gestation length.

Subsequently, a dose titration study (Figs. 17-2, 17-3, and 17-4) was conducted to determine the

minimum effective dose of domperidone for treating tall fescue toxicosis (Redmond et al., 1994).

Again, domperidone provided recovery from tall fescue toxicosis in gravid mares and the

minimum effective oral dose was 1.1 mg/kg body weight when administered daily for 30 d

before foaling.

16
Initiation of
5 Drug Therapy

4
Ma mmary Score

*
2
*
* *
1 *

0
-31 -24 -21 -14 -11 -4 -1 4 9 14
Days from Calculated Date of Parturition

1.1 mg/kg 1.65 mg/kg
2.2 mg/kg Endophyte-Free Control
Endophyte-Infected Control

Figure 17-2. Effects of varying levels of domperidone (1.1, 1.65 or 2.2 mg/kg, PO SID) on
mammary gland development in periparturient (near to parturition date) mares grazing E+ tall
fescue pastures. Day –31 represents the average number of days prior to the calculated date of
parturition when pretreatment samples were obtained (pretreatment samples obtained 1.2 d
before initiation of drug treatment). Stars indicate first detectable difference (P< .05) from
pretreatment values within treatment. Numbers indicate number of animals remaining in
treatment group when sample was obtained (from Redmond, 1994).

17
70 Initiation of Calculated
Drug Date of Mandatory
Therapy Parturition Removal Date (+7
60 days)

50 * 3
2
Prolactin (ng/ml)

40
2
30 3 3
*
* 3 1
20 1
2
10 3 1
2

0
-31 -24 -21 -14 -11 -4 -1 4 9 14
Days from Calculated Date of Parturition

1.1 mg/kg 1.65 mg/kg
2.2 mg/kg Endophyte-Free
Endophyte-Infected

Figure 17-3. Effect of E+ fescue and domperidone (1.1, 1.65, or 2.2 mg/kg, PO, SID) treatment
on serum prolactin levels in gravid mares. First detectable differences (P< .05) from pre-
treatment levels are indicated by stars. Unless otherwise indicated, data points represent 4
mares/treatment. Mares which were not showing signs of impending parturition 7 d after
the calculated date of parturition, as determined by veterinary examination, were
relocated to an E- pasture (from Redmond, 1994).

18
Calculated Date
Initiation of of Parturition Mandatory
25
Drug Therapy Removal Date (+7
2
days)
3 1
20
1
Progestagen (ng/ml)

3* 3 2
3 1
15
2
* 2ﾅ 1

10 3

0
-31 -24 -21 -14 -11 -4 -1 4 9 14
Days from Calculated Date of Parturition

1.1 mg/kg 1.65 mg/kg 2.2 mg/kg
Endophyte-Free Endophyte-Infected

Figure 17-4. Effect of E+ fescue and domperidone (1.1, 1.65, or 2.2 mg/kg, PO, SID) treatment
on serum progestagen levels in gravid mares. First detectable differences (P< .05) from pre-
treatment levels are indicated by stars. Unless otherwise indicated, data points represent 4 mares
per treatment (dagger indicates number of mares in EF group). Mares which were not showing
signs of impending parturition 7 d after the calculated date of parturition, as determined by
veterinary examination, were relocated to E- pasture (from Redmond, 1994).

In a field study (Cross et al., 1999), domperidone was administered to 1,423

periparturient mares grazing tall fescue in several U.S. states. Veterinarians and/or horse owners

reported the drug to be 95% effective in prevention of the signs of fescue toxicosis. Mares

consuming the drug in a preventative mode did not experience increased gestation, dystocia,

agalactia or lower than normal milk production, retained placentas, premature placental

separations, dead, weak, or dysmature foals, as had been observed in non-treated control mares.

19
Mechanism of action of domperidone for treating equine fescue toxicosis. The action of

domperidone as a D2 dopamine receptor blocker prevents the ergot alkaloids from mimicking

dopamine actions. The most apparent action of dopamine and the ergot alkaloids in the

fescue/endophyte symbiont is their prolactin lowering effect. With administration of

domperidone to mares consuming E+ tall fescue, prolactin returned to normal levels and even

increased above normal levels in most instances (Redmond et al., 1994). Certainly prolactin is a

major factor in equine fescue toxicosis; however, as demonstrated in the preceding review of

endocrine effects of E+ fescue, prolactin is only one of many hormones that are influenced.

Prolactin, progestogens and estrogen are certainly major factors in the milk production maladies

observed in E+ mares – and administration of domperidone returns these hormones to near

normal levels and functions. In addition, the effect of domperidone on peripheral circulation as

an alpha-1 receptor antagonist provides for its remediation of the negative microcirculatory

effects of the alkaloids.

Since the hypothalamic-pituitary-adrenal axis (HPA) of the fetus in mares consuming E+

tall fescue appears to be compromised, resulting in prolonged gestation lengths and the

associated problems, domperidone may be having some effect on the HPA system. This

hypothesis is borne out by the fact that mares that receive domperidone while grazing E+ tall

fescue foal at or near their expected foaling date with normal, healthy foals.

Adrenocorticotrophic hormone (ACTH) levels in foals from mares consuming E+ fescue are low.

Since ACTH is the stimulus for adrenal cortisol release, and since normal fetal adrenal cortisol

levels appear to be necessary to trigger parturition, we can speculate that domperidone may be

affecting this system. Zerbe et al. (1993) administered domperidone to dogs (Canis familiaris)

and observed an enhanced ACTH response to corticotrophic releasing hormone (CRH)

20
injections. Thus, domperidone could be reversing the effects of E+ tall fescue on gestation length

by causing an increase in adrenal cortisol through CRH stimulated release of ACTH. Direct

evidence to confirm this theory does not exist.

ACKNOWLEDGMENT

The author wishes to express appreciation to Dr. A.F. Parlow of the National Hormone

and Pituitary Program, UCLA Medical Center, Torrance, CA, for supplying the antigen and

antisera for the equine prolactin assays conducted at Clemson University.

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