UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington's disease and multiple sclerosis, but fails to delay/arrest the progression of different motor-related disorders.
To date, UCM707, (5Z,8Z,11Z,14Z)-N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro and in vivo as inhibitor of the endocannabinoid uptake. This may enable this compound to potentiate endocannabinoid transmission, with minimal side effects, in the treatment of several neurological disorders. In the present study, we examined whether the treatment with UCM707 produced beneficial effects, as other cannabinoid-related compounds have already shown, to alleviate motor deterioration or to delay/arrest neurodegeneration, in several models of neurological diseases such as Huntington's disease (HD), Parkinson's disease (PD) and multiple sclerosis (MS). UCM707 exhibited a notable anti-hyperkinetic activity in a rat model of HD generated by bilateral intrastriatal application of 3-nitropropionic acid. This effect was possibly associated with an amelioration of GABA and glutamate deficits induced by the toxin in the globus pallidus and the substantia nigra, respectively. However, UCM707 did not protect against the death of GABAergic neurons that occurs in rats with striatal atrophy generated by unilateral application of malonate, another animal model of HD, which is more useful to test neuroprotective strategies. In addition, UCM707 did not provide neuroprotection in rats with unilateral lesions of the nigrostriatal dopaminergic neurons caused by 6-hydroxydopamine, a rat model of PD. This was possibly due to the fact that UCM707 is devoid of anti-oxidant properties since another uptake inhibitor, AM404, that has these properties acted as a protective agent. Lastly, UCM707 was also unable to inhibit the development of the neurological impairment of rats with experimental autoimmune encephalomyelitis (EAE), an acute model of MS. However, UCM707, like other endocannabinoid uptake inhibitors reported previously, significantly reduced spasticity of the hindlimbs in a chronic relapsing EAE mice, a chronic model of MS. In summary, UCM707 might be a promising compound in HD to alleviate motor symptoms, which represents an important goal considering the current lack of efficient pharmacological treatments in this basal ganglia disorder. However, the compound was unable to delay neurodegeneration in this disorder and also in PD. In addition, UCM707 did not produce any neurological recovery from inflammatory attack in an EAE rat model of MS, although it retained the classic anti-spastic action shown by other uptake inhibitors in the EAE mouse model of this disease.
de Lago
Eva
E
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Fernández-Ruiz
Javier
J
Ortega-Gutiérrez
Silvia
S
Cabranes
Ana
A
Pryce
Gareth
G
Baker
David
D
López-Rodríguez
Mariluz
M
Ramos
José Antonio
JA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000627:therapeutic use*; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000382:microbiology; D063388:Endocannabinoids; D005106:Exploratory Behavior / Q000528:radiation effects; D005663:Furans / Q000627:therapeutic use*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008314:Malonates; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy*; D009574:Nitro Compounds; D016627:Oxidopamine; D053284:Polyunsaturated Alkamides; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005663:Furans; D008314:Malonates; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D009574:Nitro Compounds; D053284:Polyunsaturated Alkamides; D011422:Propionates; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; C030290:malonic acid; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; C015392:3-nitropropionic acid; C078814:anandamide; D004298:Dopamine