Treatment Of Huntington Disease

The Parkinson's-Reversing Breakthrough

What is Parkinsons Disease

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A. Symptomatic Therapy

Currently, only symptomatic therapy is available for HD.96 The major goals of symptomatic therapy are to control psychosis, treat depression and suicidal tendencies, and possibly control the severity of chorea and other motor manifestations. Dopaminergic and serotonergic receptor blockade with typical and atypical antipsychotics have been the major source symptomatic therapy for HD patients. Among the drugs that are commonly used are haloperidol, risperidol, quetiapine, olanzapine, and clozaril.97-100 Anti-dopaminergic agents appear to be ineffective in the treatment of chorea. However, long-term use of typical antipsychotics may also complicate the course of the disease by inducing either drug-induced Parkinson's disease and/or tardive dyskinesias and tardive dystonia. Severe depression is treated with SSRIs and other antidepressants.

B. Experimental Therapy 1. Anti-Glutaminergic Drugs

Based on the theory that glutamate excitotoxicity plays a major role in progressive degeneration of spiny striatal neurons,101 several drugs that decrease glutamatergic transmission have been tried as symptomatic treatment as well as their potentials as neuroprotective agents.102 Among these, riluzole, a drug that inhibits glutamate release and induces neuroprotection in 3-nitroproprionic acid,103 quinolinic acid104 and in transgenic models of HD,105 has not demonstrated significant and sustained benefit in human clinical trials.106-108 Remacemide and amantadine, two noncompetitive NMDA antagonists, and lamotrigine, an antiepileptic that inhibits glutamate release, might offer transient symptomatic improvement,109,110 but do not have neuroprotective properties.

2. Mitochondrial Protectants

The theory that oxidative stress resulting from mito-chondrial dysfunction111 may play a role in striatal neuronal death in HD is reinforced by the observation that in HD patients complex II is deficient,112,113 and that 3-nitropropri-onic acid,114,115 a specific and an irreversible inhibitor of complex II, and malonate, another complex II inhibitor, replicate several pathogenic mechanisms observed in the spiny neurons of the striatum of HD patients. A dose of 600 mg of coenzyme Q10, a mitochondrial protector, has been shown to be marginally effective in HD.116

3. Anti-Apoptotic Drugs

Glutamate toxicity and mitochondrial dysfunction together might ultimately induce the molecular cascades that are involved in apoptosis. Investigators have tried minocy-cline and doxycycline, caspase inhibitors, in transgenic models, but the results are inconclusive.117-120

4. Transcriptional Regulators

The histone deacetylase (HDAC) inhibitors are a promising new avenue for the treatment of HD. The earliest step of neurodegeneration might be the accumulation of the polyQ tracts in the cytoplasm followed by the entry of fragments into the nucleus, which ultimately may interfere with several transcriptional factors necessary for normal function and survival of spiny neurons of the striatum. This may lead ultimately to cell death. The HDAC inhibitors are a new class of drugs, several of which are already in clinical trials to treat different types of cancers,121 that can reactivate the expression of suppressed genes for transcription factors and might help to prevent neurotoxicity. HDAC inhibitors have been shown to "arrest" polyQ toxicity in cell culture,122 yeast,123 Drosophila,124 and mouse models of HD,125 and improve motor function in the R6/2 HD mouse model.126

5. Restorative Therapy

Restoration of striatal dysfunction by administering growth factors, including ciliary neurotrophic factor, nerve growth factor, BDNF, NT3, or by transplanting xenografts, human fetal cells or stem cells, has provided mixed results.127-131

Acknowledgment

This work was supported by the Grace Benson Research Fund.

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