Amyotrophic lateral sclerosis (ALS), or motor neuron disease (MND), is a rapidly progressive, fatal neurodegenerative condition characterized by loss of upper and lower motor neurons in the brain and spinal cord. The terms ALS and MND are often used inter-changeably to cover the different clinical syndromes, which include upper and lower motor neuron disorder, progressive bulbar palsy, and pseudo-polyneuritic form.
Degeneration of lower motor neurons (LMN) in the anterior horns of spinal cord and brainstem leads to progressive muscular atrophy and eventually to death within a few years due to respiratory insufficiency. During the course of the disease, the involvement of tongue and pharynx muscles causes swallowing impairment with marked drooling, need of parenteral or enteral feeding, and finally gastrostomy. Denervation of laryngeal muscles causes loss of speech. Cramps and fasciculation typically occur from the early phases of the disease. Degeneration of upper motor neurons (UMN) in the brain cortex causes pyramidal tract dysfunctions including clonus, Babinski sign, hypertonia, and loss of dexterity that further limit patients' daily activities.
The incidence of ALS varies from 0.2 to 2.5 cases per 100,000 per year, although estimates vary between countries, likely reflecting a combination of availability of medical services, diagnostic accuracy, and demo-graphic characteristics of the area. Increasing life expectancy and improvements in standards of treatment and care will also result in an increased incidence of ALS. Globally, the overall rate is approximately 2 per 100,000. Its prevalence is approximately of 7 per 100,000. In Italy, the reported incidence of ALS is 2.2 cases/100,000/year.
There is currently no cure for ALS. Despite initial positive results in preclinical and early clinical studies, large-scale clinical trials with all agents except riluzole failed to demonstrate a clinically meaningful therapeutic effect in patients with ALS. Riluzole at the dose of 100 mg/day showed a significant difference on survival (6.4%; gain of 3 months) and slowed deterioration in muscle strength.
Primary involvement of apoptotic mechanisms has important implications in selecting drug candidates for therapy in ALS. Recent preclinical studies have demonstrated that TUCA is endowed with antioxidant, antiapoptotic and neuroprotective activities. In particular, TUDCA can cross the blood-brain-barrier and has been shown to exert a significant therapeutic effect in a model of HD mice.
Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in humans at very low levels. TUDCA is synthesized in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA), which is commonly used as a bile acid replacement therapy for the treatment of certain cholestatic syndromes.
The main pharmacological activity of TUDCA consists in its ability in increasing the cholesterol solubilising activity of bile, thus transforming "lithogenic" bile in "non-lithogenic" or "litholytic" bile.
TUDCA inhibits mitochondrial-associated apoptosis via many pathways: 1) it inhibits the mitochondrial permeability transition (MPT) and cytochrome C release, 2) it inhibits mitochondrial membrane depolarization, and 3) it antagonizes Bax translocation from the mitochondria and caspase activation in hepatocytes and brain. TUDCA may also ease oxidative stress.Study relevant TUDCA pharmacology consists in its antioxidant, antiapoptotic and neuroprotective activities evidenced in preclinical studies.
Recent reports have shown that hydrophilic bile acids, such as UDCA and TUDCA, can prevent hepatic cytotoxicity through several mechanisms. For example, TUDCA prevents the production of reactive oxygen species and thus acts as an antioxidant. Additionally, TUDCA mitigates mitochondrial insufficiency and toxicity, and prevents apoptosis, in part, by inhibiting Bax translocation from cytosol to the mitochondria. In hepatocytes, this inhibition results in reduced mitochondrial membrane perturbation, release of cytochrome c, and activation of downstream caspases. TUDCA reduced cytotoxicity in neurons through similar mechanisms, as well as mitochondrial pathways that are independent of the permeability transition. TUDCA prevented striatal degeneration and ameliorated locomotor and cognitive deficits in the in vivo 3-nitropropionic acid (3-NP) rat model of HD. Intracellular inclusions were significantly reduced, and the TUDCA-treated mice showed improved locomotor and sensorimotor abilities.
In addition, the antiapoptotic and cytoprotective effects of TUDCA have been tested in models of acute stroke. The possibility that TUDCA exerts an antiapoptotic action by ameliorating mitochondrial function raises the issue whether other neurological disorders, including Friedreich's ataxia, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease, can benefit by the administration of TUDCA. This drug is a candidate neuroprotective agent for a variety of chronic neurodegenerative conditions.
