<sup>120</sup>

Fig. 8. Time to the onset of coma in rats with ammonia-precipitated encephalopathy.

these animals.

Time (min)

%

enrichment

16

12

8

**\***

#

4

0

Elevated brain lactate is a phenomenon which is characteristic of both human and experimental HE. As an indirect measurement of mitochondrial Krebs cycle metabolism, we measured the de novo synthesis of lactate from 13C-labelled glucose in rats with ammoniaprecipitated encephalopathy without and with treatment with L-carnitine (Fig. 9). The data showed that treatment with L-carnitine significantly eliminated the rise in brain lactate in

**PCA PCA+Carnitine**

These preliminary data demonstrate that in chronic HE, L-carnitine acts on both brain and muscle by improving mitochondrial metabolism. These data further demonstrate that Lcarnitine prevents increased lactate synthesis in ammonia-precipitated encephalopathy,

which parallels a significant increase in the time to coma.

Fig. 6. Labelling of metabolites from [1-13C]glucose. Label distribution in glycolytic and TCA cycle intermediates during metabolism of [1-13C]glucose. A single turn of the TCA cycle from pyruvate via PC (pyruvate carboxylase) or PDH (pyruvate dehydrogenase) to 2 oxoglutarate and subsequently glutamate and glutamine is considered. A description of the pathways leading to the different isotopomers is provided in the text. LDH: lactate dehydrogenase; ALAT: alanine aminotransferase; GDH: glutamate dehydrogenase; GS: glutamine synthetase.

**[1-13C]glucose**

**3 2**

**6**

**5 4**

o

*glycolysis*

**acetyl-CoA**

*PDH*

*(astrocytes+neurons)*

**lactate pyruvate alanine** *LDH ALAT*

> **1 2 3**

*PC*

**aspartate** oxaloacetate citrate

*(astrocytes)*

Fig. 6. Labelling of metabolites from [1-13C]glucose. Label distribution in glycolytic and TCA cycle intermediates during metabolism of [1-13C]glucose. A single turn of the TCA cycle from pyruvate via PC (pyruvate carboxylase) or PDH (pyruvate dehydrogenase) to 2 oxoglutarate and subsequently glutamate and glutamine is considered. A description of the

*TCAcycle*

**glutamine glutamate glutamate glutamine** *PC PDH*

2-oxoglutarate

*GDH*

*GS GS*

**1 2 3**

pathways leading to the different isotopomers is provided in the text. LDH: lactate dehydrogenase; ALAT: alanine aminotransferase; GDH: glutamate dehydrogenase; GS:

glutamine synthetase.

**1 2 3**

Fig. 7. Effect of L-carnitine on mitochondrial metabolism in rats with mild HE. [U-13C]glucose flux through the Krebs cycle was measured by the *de novo* synthesis of glutamate through PDH 12 hours after the last administration of L-carnitine or saline.

Fig. 8. Time to the onset of coma in rats with ammonia-precipitated encephalopathy.

Elevated brain lactate is a phenomenon which is characteristic of both human and experimental HE. As an indirect measurement of mitochondrial Krebs cycle metabolism, we measured the de novo synthesis of lactate from 13C-labelled glucose in rats with ammoniaprecipitated encephalopathy without and with treatment with L-carnitine (Fig. 9). The data showed that treatment with L-carnitine significantly eliminated the rise in brain lactate in these animals.

These preliminary data demonstrate that in chronic HE, L-carnitine acts on both brain and muscle by improving mitochondrial metabolism. These data further demonstrate that Lcarnitine prevents increased lactate synthesis in ammonia-precipitated encephalopathy, which parallels a significant increase in the time to coma.

L-carnitine in Hyperammonemia and Hepatic Encephalopathy 383

The treatment of HA is uncertain and mostly directed to reducing the level of circulating ammonia. There is currently no therapy designed to counteract the molecular effects of ammonia. A further question remains as to whether the protective effects of L-carnitine against the toxicity of ammonia are systemic. In most studies, L-carnitine reduces circulating ammonia levels, suggesting a systemic effect of L-carnitine. For example, L-carnitine has been shown to have direct effects on the liver in patients with steatosis (Romano et al., 2008), and Benzerrouk and Qureshi (2001) demonstrated that acetyl-L-carnitine has a modulating effect on several hepatic mitochondrial matrix and inner membrane proteins that are modified by HA in the spf mutant mouse. On the other hand, L-carnitine seems to have direct effects on cerebral metabolism in valproic acid toxicity in the absence of

Another question to be clarified is why the effects of L-carnitine differ from its derivative acetyl-L-carnitine. When compared with L-carnitine, for example, acetyl-L-carnitine better preserved ATP in the brain of hyperammonemic mice, while it lowered ammonia in the blood and brain less markedly. One reason for this apparent discrepancy may lie in the use of the acetyl residue by the brain. This, on the other hand, points to an additional effect of this L-carnitine derivative on astrocytic energy metabolism, since acetate is taken up selectively by astrocytes while neurons do not use acetate (Waniewski and Martin, 1998; Zwingmann & Leibfritz, 2003). On the other hand, there could be a close correlation between changes in astrocytic energy metabolism and neuronal (dys)function. In particular, L-carnitine exerts its effects in part by changes in NMDA receptor activation. Ammonia and extracellular glutamate cause an overactivation of this receptor, which in turn produces NO resulting in nitration-mediated inhibition of proteins such as the ammonia-detoxifying glutamine synthetase in the astrocytes. Improved energy metabolism in the astrocytes might counteract this deficit as well as a possible effect of ammonia on the astrocytic TCA cycle (Chatauret et al., 2003). The molecular and cell-specific energetic effects of L-carnitine and

Taken together, these results show that L-carnitine and its analogues do have the potential to suppress the neurotoxicity of ammonia. The fact that the action of acetyl-L-carnitine may differ from that of L-carnitine suggests that the classical function of L-carnitine is not the sole mechanism underlying the suppression of the neurotoxicity of ammonia (Matsuoka & Igisu, 1993). However, further investigations are required to clarify the molecular mechanisms that lead to the protective effects of L-carnitine and its derivates in both experimental HA and human HE. Other studies may also optimize the dosage and time of administration of L-carnitine. Analysis of selected L-carnitine trials compared to currently accepted therapies suggests that L-acyl-carnitine is promising as a safe and effective treatment for HE, and further trials of this drug are warranted (Shores & Keeffe, 2008). Since it is a low-cost agent with few side effects, further clinical trials could prove to be promising in evaluating the broader use of L-carnitine and derivatives in patients with minimal or

This work was funded by the Canadian Instituts for Health Research (CIHR). Dr. Zwingmann is a recipient of supporting awards from the Quebec Ministry of Education, the Programme québécois de bourses d'excellence, the Deutsche Forschungsgemeinschaft

hepatocellular dysfunction (Sztajnkrycer, 2002).

acetyl-L-carnitine therefore require further clarification.

ammonia-precipitated HE.

**6. Acknowledgements** 

Fig. 9. Effect of L-carnitine on glycolytic lactate synthesis in rats with ammonia-precipitated encephalopathy. [U-13C]glucose flux through glycolysis was measured by the *de novo* synthesis of lactate.

#### **5. Concluding remarks**

To date, few studies have investigated the effect of L-carnitine and its derivates in human hyperammonemic syndromes and HE. However, in hyperammonemic animal models and ammonia-exposed cultured neurons L-carnitine has been shown to counteract some of the neurotoxic effects of ammonia. These data clearly show that L-carnitine is able to reduce ammonia levels, increase energy metabolism and decrease mortality. These studies further prove that HA is a key factor in HE. A protective effect of L-carnitine against disordered mental function and ammonia-precipitated encephalopathy was also observed in cirrhotic patients with HE, together with lowered circulating ammonia levels. These clinical trials are promising as they clarify that L-carnitine can reduce ammonia levels and improve patient performance in HE. The molecular mechanisms of the action of L-carnitine have not yet been fully elucidated, although the results suggest an effect on neuronal function in HE.

HE is a disorder that morphologically primarily affects the astrocytes (Norenberg, 1998). The dysfunction of astrocytes includes deficits in their ability to take up glutamate from the extracellular space, which may lead to abnormal glutamatergic neurotransmission. However, a series of studies has also demonstrated that ammonia directly causes disorders in neuronal function and neurotransmitter homeostasis by acting on glutamatergic receptors and by synthesis of neurotransmitters, i.e. glutamate and GABA. Furthermore, in recent studies an inhibition of neuronal energy metabolism in the TCA cycle has been proposed. Animal and cell culture studies have indicated that ammonia impairs neuronal function via altered metabolism and ultimately NMDA receptor activation, and that L-carnitine and NMDA receptor antagonists have the potential to preserve neuronal function during HA. Lcarnitine and its derivates increase energy metabolism via the TCA cycle by activation of fatty acid oxidation. They are able to change the activities of several enzymes involved in fatty acid metabolism, increase the synthesis of phospholipids and provide acetyl groups for the synthesis of acetylcholine. Furthermore, they can modify membrane fluidity and surface charge, which lead to altered activity of membrane transporter and enzymes. Since the brain can sustain part of its energy metabolism by fatty acid catabolism, the role of astrocytes and their energy metabolism in L-carnitine therapy needs further experimental clarification.

#

\* P < 0.05 # P < 0.05 PCA-Carnitine vs. PCA

**Lactate synthesis**

**\***

Fig. 9. Effect of L-carnitine on glycolytic lactate synthesis in rats with ammonia-precipitated encephalopathy. [U-13C]glucose flux through glycolysis was measured by the *de novo*

**Sham PCA PCA+Carnitine**

To date, few studies have investigated the effect of L-carnitine and its derivates in human hyperammonemic syndromes and HE. However, in hyperammonemic animal models and ammonia-exposed cultured neurons L-carnitine has been shown to counteract some of the neurotoxic effects of ammonia. These data clearly show that L-carnitine is able to reduce ammonia levels, increase energy metabolism and decrease mortality. These studies further prove that HA is a key factor in HE. A protective effect of L-carnitine against disordered mental function and ammonia-precipitated encephalopathy was also observed in cirrhotic patients with HE, together with lowered circulating ammonia levels. These clinical trials are promising as they clarify that L-carnitine can reduce ammonia levels and improve patient performance in HE. The molecular mechanisms of the action of L-carnitine have not yet been fully elucidated, although the results suggest an effect on neuronal function in HE.

HE is a disorder that morphologically primarily affects the astrocytes (Norenberg, 1998). The dysfunction of astrocytes includes deficits in their ability to take up glutamate from the extracellular space, which may lead to abnormal glutamatergic neurotransmission. However, a series of studies has also demonstrated that ammonia directly causes disorders in neuronal function and neurotransmitter homeostasis by acting on glutamatergic receptors and by synthesis of neurotransmitters, i.e. glutamate and GABA. Furthermore, in recent studies an inhibition of neuronal energy metabolism in the TCA cycle has been proposed. Animal and cell culture studies have indicated that ammonia impairs neuronal function via altered metabolism and ultimately NMDA receptor activation, and that L-carnitine and NMDA receptor antagonists have the potential to preserve neuronal function during HA. Lcarnitine and its derivates increase energy metabolism via the TCA cycle by activation of fatty acid oxidation. They are able to change the activities of several enzymes involved in fatty acid metabolism, increase the synthesis of phospholipids and provide acetyl groups for the synthesis of acetylcholine. Furthermore, they can modify membrane fluidity and surface charge, which lead to altered activity of membrane transporter and enzymes. Since the brain can sustain part of its energy metabolism by fatty acid catabolism, the role of astrocytes and their energy metabolism in L-carnitine therapy needs further experimental clarification.

synthesis of lactate.

%

enrichment

**5. Concluding remarks** 

The treatment of HA is uncertain and mostly directed to reducing the level of circulating ammonia. There is currently no therapy designed to counteract the molecular effects of ammonia. A further question remains as to whether the protective effects of L-carnitine against the toxicity of ammonia are systemic. In most studies, L-carnitine reduces circulating ammonia levels, suggesting a systemic effect of L-carnitine. For example, L-carnitine has been shown to have direct effects on the liver in patients with steatosis (Romano et al., 2008), and Benzerrouk and Qureshi (2001) demonstrated that acetyl-L-carnitine has a modulating effect on several hepatic mitochondrial matrix and inner membrane proteins that are modified by HA in the spf mutant mouse. On the other hand, L-carnitine seems to have direct effects on cerebral metabolism in valproic acid toxicity in the absence of hepatocellular dysfunction (Sztajnkrycer, 2002).

Another question to be clarified is why the effects of L-carnitine differ from its derivative acetyl-L-carnitine. When compared with L-carnitine, for example, acetyl-L-carnitine better preserved ATP in the brain of hyperammonemic mice, while it lowered ammonia in the blood and brain less markedly. One reason for this apparent discrepancy may lie in the use of the acetyl residue by the brain. This, on the other hand, points to an additional effect of this L-carnitine derivative on astrocytic energy metabolism, since acetate is taken up selectively by astrocytes while neurons do not use acetate (Waniewski and Martin, 1998; Zwingmann & Leibfritz, 2003). On the other hand, there could be a close correlation between changes in astrocytic energy metabolism and neuronal (dys)function. In particular, L-carnitine exerts its effects in part by changes in NMDA receptor activation. Ammonia and extracellular glutamate cause an overactivation of this receptor, which in turn produces NO resulting in nitration-mediated inhibition of proteins such as the ammonia-detoxifying glutamine synthetase in the astrocytes. Improved energy metabolism in the astrocytes might counteract this deficit as well as a possible effect of ammonia on the astrocytic TCA cycle (Chatauret et al., 2003). The molecular and cell-specific energetic effects of L-carnitine and acetyl-L-carnitine therefore require further clarification.

Taken together, these results show that L-carnitine and its analogues do have the potential to suppress the neurotoxicity of ammonia. The fact that the action of acetyl-L-carnitine may differ from that of L-carnitine suggests that the classical function of L-carnitine is not the sole mechanism underlying the suppression of the neurotoxicity of ammonia (Matsuoka & Igisu, 1993). However, further investigations are required to clarify the molecular mechanisms that lead to the protective effects of L-carnitine and its derivates in both experimental HA and human HE. Other studies may also optimize the dosage and time of administration of L-carnitine. Analysis of selected L-carnitine trials compared to currently accepted therapies suggests that L-acyl-carnitine is promising as a safe and effective treatment for HE, and further trials of this drug are warranted (Shores & Keeffe, 2008). Since it is a low-cost agent with few side effects, further clinical trials could prove to be promising in evaluating the broader use of L-carnitine and derivatives in patients with minimal or ammonia-precipitated HE.

#### **6. Acknowledgements**

This work was funded by the Canadian Instituts for Health Research (CIHR). Dr. Zwingmann is a recipient of supporting awards from the Quebec Ministry of Education, the Programme québécois de bourses d'excellence, the Deutsche Forschungsgemeinschaft

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### *Edited by Radu Tanasescu*

The book project "Miscellanea on Encephalopathies-a second look" aims to cover some of the important aspects regarding metabolic, hypoxic, neoplasm- and drug-related encephalopathies, by transmitting valuable information filtered through the real life clinical and research experience of the authors.

Photo by cooperr007 / iStock

Miscellanea on Encephalopathies - A Second Look

Miscellanea on

Encephalopathies

A Second Look

*Edited by Radu Tanasescu*