Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aß42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

Stimulation of the globus pallidus internus in the treatment of Parkinson's disease: Long-term results of a monocentric cohort.

BACKGROUND: Pallidal deep brain stimulation (DBS) has shown to be beneficial in patients with advanced levodopa-responsive Parkinson's disease (PD) in several short-term studies. However, reported long-term outcomes of pallidal DBS for PD are limited and contradictory. METHODS: Eighteen consecutive PD patients were treated with unilateral or bilateral stimulation of the internal part of the globus pallidus (GPi). Assessments were carried out before and six months after neurosurgery, and annually thereafter for up to 16 years (mean follow-up time: 6 years). Primary outcomes included motor signs (Unified PD Rating Scale [UPDRS]-III), activities of daily living (ADL, UPDRS-II), and levodopa-induced motor complications (UPDRS-IV). RESULTS: The results show that GPi stimulation improves levodopa-responsive PD motor signs (UPDRS-III), levodopa-induced motor complications (UPDRS-IV), and ADL (UPDRS-II) in advanced PD. Among motor signs, tremor showed the best response to pallidal stimulation. Levodopa-induced motor complications and tremor showed improvements for more than 10 years after neurosurgery. CONCLUSIONS: The overall findings in our cohort demonstrate that pallidal stimulation is effective in reducing parkinsonian motor signs (UPDRS-III), particularly in the 'off'-medication state. Although the beneficial effects on bradykinesia, rigidity and ADL may be limited to 5-6 years, the follow up results indicate that the improvements of levodopa-induced motor complications (UPDRS-IV) and tremor can be sustained for more than 10 years.

Increased basal-ganglia activation performing a non-dystonia-related task in focal dystonia.

BACKGROUND AND PURPOSE: We tried to determine whether altered sensorimotor cortex and basal-ganglia activation in blepharospasm (BSP) and cervical dystonia (CD) are restricted to areas directly responsible for the innervation of dystonic muscles, or whether impairment in focal dystonia reaches beyond these direct associations supporting a more global disturbance of sensory and motor control in focal dystonia. METHODS: Twenty patients with focal dystonia (11 BSP, 9 CD) and 14 healthy controls were investigated with functional magnetic resonance imaging (fMRI) performing a simple grip force forearm contraction task. RESULTS: BSP and CD patients and healthy controls showed similar activation in the pre-motor, primary motor and primary sensory cortex, whilst basal-ganglia activation was increased in BSP and CD with related activation patterns compared with controls. BSP patients had increased activation in the thalamus, caudate nucleus, putamen and lateral globus pallidus, whilst CD patients showed increased activation in the caudate nucleus, putamen and thalamus. No differences in applied grip force were detected between groups. CONCLUSIONS: In both, BSP and CD, increased basal-ganglia activation could be demonstrated in a task not primarily involving the dystonic musculature affected by these disorders. Comparable activation changes may also indicate a common pathway in the pathophysiology in BSP and CD.