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

Abstract

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 (AD) and Huntington’s diseases (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae (S. cerevisiae). We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein, 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-synuclein clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wildtype mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-synuclein, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-synuclein in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-synuclein accumulation in transgenic mouse models of α-synuclein neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, that might yield clinical benefit for synucleinopathies including PD, Lewy body dementia, REM sleep disorder, and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Therapeutic prospects for Parkinson disease

“…Similar observations have been noted with agents such as trehalose that promote autophagy in a TORindependent manner 91 . Latreperdine (Dimebon®) is an antihistamine that has been widely used in Russia and promotes autophagy and clearance of α-synuclein 92 . Latreperdine been tested in short-term clinical trials in AD and failed to meet the primary endpoint, but was well tolerated with no significant toxicity.…”

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

“…In contrast, Dimebon's suppression of TBHP-induced lipid peroxidation is maximal at 0.4 mM [13]. Moreover, Dimebon decreased mitochondrial lipid peroxidation induced by calcium and amyloid β-peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in contrast to cyclosporine A [13,14] and decreased spontaneous lipid peroxidation in rat brain homogenates (Fig. 4), indicative of an anti-aging component.…”

“…Bharadwaj et al similarly found that Dimebon facilitated removal of Aβ42-GFP levels via the autophagy pathway in yeast [24]. Chronic administration of Dimebon reportedly induced autophagy and α-synuclein removal in mouse brain [26].…”

“…In the nanomolar range, Dimebon induces the migration of mitochondria to neurites of hippocampal neurons and stimulates neurite outgrowth [15]. At higher concentrations (100 nM), mitochondria are protected from the toxic effects of amyloid β-peptide , while at micromolar concentrations, cerebellar granular neurons are stabilized from the toxic effect of amyloid β-peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) [10,15].…”

“…However, the role of glutamate receptors and cholinesterases in Dimebon's neuroprotective action has been questioned [12]. Recent studies involving various experimental systems ranging from cellular to transgenic animal models of dementia-type neurodegeneration demonstrate that Dimebon stabilizes mitochondrial functions by preventing mitochondrial permeability transition [13][14][15][16][17], reducing accumulation of pathological proteins [18][19][20][21][22][23], and simulating autophagy [24][25][26][27], thereby showing a multimodal mechanism of action ( Table 1). All together, these findings support the re-evaluation of Dimebon's therapeutic potential and newly designed analogs as promising disease-modifying agents for neurodegenerative disorders [6,28].…”