d-Lactic acid-induced neurotoxicity in a calf model

Abstract

Lactic acidosis (DAC) occurs as a complication of short-bowel syndrome in humans and in a variety of other gastrointestinal disorders in monogastrics and ruminants. DAC is associated with signs of impaired central nervous system (CNS) function including ataxia and coma. The objective of this experiment was to determine whether either acidification of nervous tissue or d-lactic acid is responsible for decreased neurological function. Eight Holstein calves (32 +/- 11 days, 70 +/- 10 kg) were surgically catheterized with indwelling intravenous jugular and atlanto-occipital space cerebrospinal fluid (CSF) catheters and infused for 6 h in random order with isomolar dl-lactic acid (dl-LA), l-lactic acid (l-LA), hydrochloric acid (HCl), or saline. dl-LA induced ataxia after 4 h of infusion and produced the greatest obtunding of CNS function (at 7 h, score 8.0 +/- 0.4), whereas the other infusions caused neither ataxia nor scores over 1.5 (P < 0.01 from dl-LA). dl-LA induced significantly less acidemia than HCl (at 6 h pH 7.13 +/- 0.06 and 7.00 +/- 0.04, base excess -16 +/- 1 and -23 +/- 3 mmol/l, bicarbonate 11 +/- 1 and 8 +/- 1 mmol/l respectively, all P < 0.01) but greater than l-LA and saline (P < 0.01). CSF changes followed a similar but less pronounced pattern. Although HCl infusion produced a severe acidemia and CSF acidosis, only minor effects on neurological function were evident suggesting that d-lactate has a direct neurotoxic effect that is independent of acidosis. Conversely, l-LA produced only minor neurological changes.

Faecal D/L Lactate Ratio Is a Metabolic Signature of Microbiota Imbalance in Patients with Short Bowel Syndrome

“…We found, coherently with the literature, that faecal D-lactate was undetectable in healthy human faeces and the faecal L-lactate was around 1.5 mM [41], [47], [48]. D-lactate enantiomer is toxic for neurons in a manner that is independent of acidosis [49] while L-lactate is metabolized at high level by neurons. D-and L-lactate share similar pathways of transport and metabolism in the digestive tract, but in human brain tissue, D isoform seems to impair the L lactate availability, thus provoking energy deficit in neurons [23], [50].…”

D-lactic acidosis and ataxia in a man with Crohn disease

“…4,12 The accumulation of D-lactate in brain tissue because of naturally low levels of Dlactate dehydrogenase has also been hypothesized. 11 These theories are not supported by a study showing that infusion of D-lactate into healthy volunteers to a serum concentration of 6 mmol/L did not cause neurologic symptoms. 9 This finding suggests the presence of other mediators associated with D-lactate.…”

“…A reduction in serum pH alone is insufficient to explain such manifestations, given that acidosis of comparable severity from other causes does not always result in this presentation. Various theories have been advanced, including suggestions that low pH may affect intraneural metabolism of L-lactate, which is the preferred substrate of nervous aerobic metabolism, 11 or may inhibit central and peripheral neurotransmitter production. 4,12 The accumulation of D-lactate in brain tissue because of naturally low levels of Dlactate dehydrogenase has also been hypothesized.…”

Abomazum Deplasmanlı Sütçü Sığırlarda D (-) ve L (+) Laktik Asit ile Bazı Biyokimyasal ve Hematolojik Parametrelerin Diagnostik ve Prognostik Açıdan Öneminin Belirlenmesi

“…RDA'lı ineklerin operasyon öncesi D-LA düzeyleri LDA ve kontrol grubundan daha yüksektir (P<0.001). İshalli buzağılarda HCO 3 -kaybı, metabolik asidozis sonucu laktik asit metabolizmasındaki enzimlerin inaktivasyonu 13,19 , ruminal asidozis, bağırsaklardaki patojenlerin yol açtığı villus atrofisi ve malabsorbsiyon nedeniyle 28 D hiperlaktatemi oluştuğu bildirilmektedir. Bu çalışma ise, D hiperlaktatemi görülen RDA'lı ineklerin HCO 3 -ve kan pH'sı 16,19 Bu araştırmada LDA grubunun tedavi sonrası Cl -ortalama değerlerinde gözlenen artış (P<0.05), araştırmacıların 11,12,30 bulgularına benzemektedir.…”

“…Bunun nedeni, memelilerde D laktat dehidrojenaz'ın bulunmaması ve bu enzimin yerini aldığı bildirilen D-2-hidroksi asid dehidrojenazın da sınırlı bir etkiye sahip olmasıdır. D-LA'nın kan-beyin bariyerini aşarak beyinde biriktiği ve merkezi sinir sistemi üzerinde toksik etki gösterdiği bilinmektedir 13 . Kandaki laktat miktarı, abomazum volvulusunda oluşan hemodinamik ve metabolik bozuklukların derecesi ile hastanın prognozu hakkında da bilgi vermektedir [14][15][16][17] .…”