Huntington Project > SET-HD > SET-HD Compound Reviews ( DNN 3.2.2 )

Note

SET-HD compound reviews were last revised in 2006.

Updates as of March 2006 include a revised/updated version of the Cystamine review, and 5 new compound reviews were added for Cannabinoids, Cysteamine, Ethyl-EPA, Olanzapine, and Tetrabenazine.

Amantadine (AMT), Memantine (MMT, Namenda) - Thursday, June 30, 2005
Amantadine (AMT) and Memantadine (MMT) act by modulating neuronal excitotoxicity. In rats, MMT has been shown to protect against lesions induced by the injection of neurotoxins, but neither drug has been tested in transgenic mouse models. Both AMT and MMT cross the blood brain barrier. Human studies have shown limited improvement in chorea from either AMT or MMT. One small study showed that MMT may modify HD disease progression. This needs to be confirmed in more controlled, larger studies.

Ascorbic Acid (AA) - Thursday, June 30, 2005
Ascorbic Acid (AA) is a naturally occurring substance that scavenges free radicals in the CNS, thus limiting oxidative damage and excitotoxicity. In transgenic mice, AA improved performance on measures of repetitive movement without altering overall motor activity. AA crosses the BBB and has been shown to be well tolerated in humans, with a low incidence of side effects; however, no clinical studies in people with HD have been performed.

BN82451 (Ipsen) - Tuesday, May 24, 2005
BN82451 is an antioxidant and anti-inflammatory agent. Both of these properties may have a beneficial effect in HD by limiting oxidative damage, excitotoxicity, and inflammation. In transgenic mice, BN82451 was shown to improve survival, motor performance, and brain atrophy; however the motor improvement was short lived. No data are available regarding BBB permeability and no human studies have been conducted.

Cannabinoids - Monday, March 06, 2006
Cannabinoids are a class of drugs that bind to cannabinoid receptors in the brain and inhibit the uptake of endogenous cannabinoids. Through this action, it is thought that they might modify motor dysfunction and confer neuroprotection in HD patients. In 3-NP lesioned rats, several of the cannabinoids have been shown to have anti-hyperkinetic effects. There are no studies in transgenic HD mouse models. There is no human evidence suggesting that cannabinoids are effective either symptomatically or in preventing disease progression.

Coenzyme Q10 (CoQ) - Thursday, February 17, 2005
Coenzyme Q10 (CoQ) is involved in cellular energy metabolism, which is impaired in HD patients. In rats, it has been shown to be protective against the formation of lesions induced by excitotoxins. In transgenic mice, inconsistent results were seen in several studies that used CoQ in combination with remacemide (RCM). Human clinical trials showed a statistically insignificant decrease in functional decline and a significant decrease in cognitive decline. Adverse effects were mild. Studies using higher doses are planned and preliminary data suggests that HD patients may tolerate them well.

Creatine (CRE) - Thursday, February 17, 2005
Creatine (CRE) is an amino acid that is often taken as a dietary supplement and is thought to correct an energy imbalance seen in HD patients. In rats, CRE significantly decreased lesional volumes and energy depletion after administration of a mitochondrial toxin. In transgenic mice, CRE given to presymptomatic or early symptomatic animals improved survival and motor performance, reduced brain atrophy, and reduced weight loss. In human studies, it was unclear whether 10 g of CRE per day delayed declines in motor function and cognition.

Cystamine (CYS) - Updated Version - Monday, March 06, 2006
Cystamine (CYS) prevents protein aggregation by inhibiting an enzyme called transglutaminase (TG), which is elevated in HD brains. CYS may also act by other mechanisms to prevent neurodegeneration. In transgenic mice treated presymptomatically, CYS improved survival and motor behavior, reduced striatal atrophy and the formation of aggregates, and attenuated weight loss. There have been no safety studies of CYS in humans; however, CYS is converted to cysteamine in the body, which is well tolerated.

Cysteamine - Monday, March 06, 2006

Cysteamine (CYE) is a metabolite of cystamine (CYS) and is believed to act in a manner similar to CYS. There are no studies of CYE in animal models of HD. In human trials of CYE, treatment was tolerated but the studies were too small and brief to conclude anything relative to a symptomatic and/or disease-modifying effect.

Dichloroacetate (DCA) - Thursday, June 30, 2005
Dichloroacetate (DCA) is thought to be beneficial against HD because it enhances energy metabolism in cells, decreases brain lactate, and helps to clear the excitotoxin glutamate. In two types of transgenic mice, DCS treatment improved survival, motor performance, and brain atrophy, but only in late stages of the disease. DCA has been used in humans for other conditions with few side effects.

Ethyl-EPA - Monday, March 06, 2006
Ethyl EPA (EPA) is a fatty acid that improves mitochondrial function; inhibits enzymes involved in neurodegeneration, inflammation, and apoptosis; and stabilizes membranes. In HD mouse models, EPA has shown benefits in survival and motor performance, but no effect on neuronal degeneration. Human trials have suggested some mild improvement in chorea but some negative behavioral effects with low doses in symptomatic patients.

Geldanamycin (GA)/Radicicol (RA)/17-(allylamino)-17-demethoxygeldanamycin (17-AAG, NSC 330507) - Thursday, February 17, 2005
Geldanamycin (GA) is a naturally occurring substance that inhibits the aggregation of huntingtin protein in cultured neurons. It also has been shown, in culture, to inhibit glutamate-induced cell death. However, it has not yet been tested in animal models to determine if it leads to improved motor function or extended survival. An analog of GA, 17-AAG, appears to have some advantages over GA itself, including the ability to cross the blood brain barrier. 17-AAG is currently being used in early phase clinical trials in cancer patients. Studies using 17-AAG in HD animal models are suggested to determine if the compound has therapeutic potential.

HDAC Inhibitors: Sodium Butyrate(SB)/Phenylbutyrate (PB)/Suberoylanilide hydroxamic acid (SAHA) - Tuesday, May 24, 2005
HDAC Inhibitors tested include Sodium Butyrate (SB), Phenylbutyrate (PB), and Suberoylanilide hydroxamic acid (SAHA). By inhibiting histone deacetylase, these drugs facilitate gene transcription, which is repressed in the presence of the HD mutation. They may also prevent the sequestration of certain transcription factors by huntingtin aggregates. In flies, SB was shown to slow neurodegeneration. In transgenic mice, HDAC inhibitors improved survival and motor performance, and reduced striatal atrophy. These drugs are used as chemotherapeutic agents against cancer but have not yet been tested on humans with HD. A study with PB in HD patients is planned.

Lipoic Acid (LA)/Thioctic Acid - Monday, December 13, 2004
Lipoic Acid (LA) is an antioxidant that is taken as a nutritional supplement for several conditions such as preventing complications from diabetes. In cell culture it is protective against excitotoxicity and it also has been shown to be protective in rats injected with neurotoxins. In transgenic mice, it has been shown to increase survival. It is well tolerated in humans, although significant adverse effects have been seen when used in high doses. It has not yet been tested clinically in people with HD.

LITHIUM (LI) - Tuesday, May 24, 2005
Lithium (LI) is neuroprotective through several possible mechanisms, among them inhibition of excitotoxicity and apoptosis, and inhibition of an enzyme (GSK-3ß) involved in regulating cell survival. Inhibition of this enzyme also reduces nuclear fragmentation and inclusion formation. In rats, LI reduced striatal injury induced by injection of excitotoxins. In transgenic mice, LI did not improve survival or motor performance at the doses tested. Controlled human studies have shown little or no improvement in motor symptoms, cognition, or behavior for HD patients.

Minocycline (Minocin, MINO) - Monday, December 13, 2004
Minocycline (MINO) is an antibiotic that inhibits protein aggregation and apoptosis in brain cells and that has been shown to protect neuronal cells that express mutant huntingtin. In mice injected with the excitotoxin 3-NP, MINO worsened motor performance and increased fatalities. In transgenic mice, results with MINO have been inconsistent. Human clinical studies have also been inconsistent. The drug is well tolerated with few side effects.

Mithramycin (MIT) or Plicamycin - Tuesday, May 24, 2005
Mithramycin (MIT) is an antibiotic that interferes with gene transcription. It is believed to prevent neurodegeneration by interfering with the ability of the mutant huntingtin protein to cause transcriptional dysregulation. It may also prevent the transcription of cell death proteins. In transgenic mice MIT improved survival, motor performance, and brain atrophy. Brain concentrations of MIT are limited, and the drug causes significant adverse effects with continued use. Human studies with HD patients have not been conducted.

Olanzapine - Monday, March 06, 2006
Olanzapine (OLZ) is a potent dopaminergic receptor and serotonin antagonist. Through these actions, it is thought that OLZ might reduce chorea and psychotic/behavior symptoms in HD patients. There are no studies in animal models of HD. Small human studies suggest a trend toward improved UHDRS motor/chorea and behavior scores.

OPC-14117 (OPC) - Tuesday, May 24, 2005
OPC-14117 (OPC). OPC is a potent antioxidant that may limit oxidative damage and excitotoxicity. In rats injected with excitotoxins, OPC given as a pretreatment was shown to prevent the loss of striatal neurons. There have been no studies in transgenic mice. OPC readily crosses the BBB. Safety and dose-ranging studies in humans showed significant adverse effects but no improvement in outcome.

Paroxetine (Paxil, PAX) - Monday, December 13, 2004
Paroxetine (PAX) is a selective serotonin reuptake inhibitor (SSRI) and has been shown to have clinical symptomatic benefits in people with HD. PAX increases the concentration of serotonin, which stimulates neuroprotective pathways and may also stimulate other factors that increase neuronal survival. In transgenic mice, PAX delayed the onset of behavioral symptoms, improved survival and motor performance, reduced apoptosis and brain atrophy, attenuated hyperglycemia, and slowed weight loss. No clinical trials of PAX in HD patients have been conducted.

Rapamycin (RAP, Rapamune, Sirolimus)/CCI-779 - Monday, December 13, 2004
Rapamycin (RAP) is an immunosuppressant that also stimulates autophagy, resulting in the clearance of protein aggregates. It may also stabilize neurons against injury. In flies expressing mutant huntingtin protein, RAP reduced neurodegeneration. In transgenic mice, the prodrug of RAP, CCI-779 led to fewer striatal aggregates and a tendency to higher ratio of brain weight to body weight, improved motor performance, and a trend toward improved survival. In clinical trials with transplant patients, RAP and placebo both produced significant adverse effects. No clinical studies have been done in patients with HD.

Remacemide (RCM) - Thursday, June 30, 2005
Remacemide (RCM) and its active metabolite inhibit glutamate-induced excitotoxicity, which is thought to contribute to HD symptoms. In HD mouse models, RCM has prolonged survival, improved motor performance, and reduced brain atrophy, especially when given in combination with Coenzyme Q. Human studies showed no statistical benefit at the doses used, although a trend to reduce chorea was seen.

Tauroursodeoxycholic acid (TUDCA) - Thursday, February 17, 2005
Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid synthesized in the liver that inhibits mitochondrial-associated apoptosis. It may also ease oxidative stress. In rats injected with neurotoxins and in transgenic mouse models, TUDCA has been shown to protect against neuronal degeneration, improve motor performance, and slow cognitive decline. TUDCA has been used in humans to treat other conditions with adverse effects such as dyspepsia and diarrhea. It has not yet been tested clinically in people with HD.

Tetrabenazine - Monday, March 06, 2006
Tetrabenazine (TBZ) depletes neurotransmitters, particularly dopamine (DA). By modulating DA neurotransmission, TBZ is thought to reduce chorea. In MA-lesioned rats and mice, TBZ has been shown to decrease DA neuronal loss. Human trials suggest that TBZ has beneficial effects for a variety of movement disorders including chorea in HD patients. There are no data that suggest a disease-modifying effect. read more...

TREHALOSE (TRE) - Thursday, February 17, 2005
Trehalose (TRE) is a naturally-occurring substance found in many foods. It decreases protein aggregation, which has been implicated in HD. In cell models, TRE was shown to inhibit aggregation and cell death. In transgenic mice, TRE improved survival and motor performance, and reduced brain atrophy. It is well tolerated by most people with mild side effects. There have been no clinical studies in humans with HD.