Send Orders for Reprints to [email protected] Current Medicinal Chemistry, 2016, 23, 1-12 1 REVIEW ARTICLE New Therapeutic Property of Dimebon as a Neuroprotective Agent Aleksey Ustyugov1, Elena Shevtsova1, George E. Barreto2,3, Ghulam Md Ashraf 4, Sergey O. Bachurin1 and Gjumrakch Aliev1,5,6,* 1Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severniy Proezd 1, Cher- nogolovka, 142432, Russia; 2Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Uni- versidad Javeriana, Bogotá D.C., Colombia; 3Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile; 4King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Ara- bia; 5GALLY International Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San An- tonio, TX, 78229, USA; 6School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, 30097, USA Abstract: Dimebon (or Latrepirdine) was initially used as an anti-histamergic drug but later new therapeutic properties were rediscovered, adding to a growing body of “old” agents with prominent neuroprotective effects. In the present manuscript, we are focusing on our latest study on Dimebon with regard to brain’s pathological processes using in vivo protei- A R T I C L E H I S T O R Y nopathy models. In the study, neurodegenerative pathology has been attributed to a group of aggregate-prone proteins: hyperphosphorylated tau, fused in sarcoma and γ-synuclein , which Received: March 13, 2016 Revised: June 08, 2016 are involved in a number of neurological disorders. We have also presented our in vitro Accepted: July 24, 2016 model based on overexpression of an aberrant mutant form of transactive response DNA DOI: 10.2174/0929867323666160804 binding 43 kDa protein in cultured SH-SY5Y neuroblastoma cells. Dimebon treatment fol- 122746 lowed by the activation of autophagy markers resulted in reduced number of inclusion con- taining cells. The most significant effects of Dimebon appeared to be on the improving cellu- lar energy balance, mitochondria stability by increasing the threshold for nonselective mito- chondrial pore opening as well as on increased calcium retention capacity while reducing lipid peroxidation. The therapeutic potential of Dimebon and newly designed analogs show disease modifying properties and could be used to treat neurodegenerative disorders. In addi- tion, new data hint on a possible anti-aging effect and potential application of Dimebon for treatment of anxiety, ischemia and depression. Overall, our findings suggest that the most pronounced effect of Dimebon was observed when treatment was started at the early stages of disease onset and this factor needs to be taken into account while planning future clinical trials. Keywords: Dimebon, Latrepirdine, proteinopathy, neuroprotection, mitochondrial permeability transition. INTRODUCTION gress towards long term treatment options. In recent years, the steadily increasing number of failures in The drugs for the treatment of majority of neurode- clinical trials led to an alternative strategy based on re- generative disorders (NDDs) such as Alzheimer disease introduction of earlier approved medicines as route for (AD), Parkinson’s disease (PD), amyotrophic lateral modern drug research [1, 2]. Dimebon (or Latrepirdine) sclerosis (ALS), frontotemporal dementia (FTD), etc is one of those “old” drugs which has been quite effec- provide only temporary relief without any visible pro- tive in the treatment of pathological conditions differ- ing from original targets (Fig. 1) [3-5]. Several decades *Address correspondence to this author at the GALLY International ago it was marketed as a non-competitive anti- Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA; Tel: +1(440) 263-7461; histamine agent, but unexpectedly showed the ability to E-mail: [email protected] enhance cognition in a small-scale, open-label trial of 0929-8673/16 $58.00+.00 © 2016 Bentham Science Publishers 2 Current Medicinal Chemistry, 2016, Vol. 23, No. 30 Ustyugov et al. mechanistic capabilities of mitochondria which has N opened up new possibilities will make this task even more challenging [10, 11]. The lack of definitive mode N of action is hampering the attempt to understand the Cl remarkable discrepancies in clinical trials and also Cl eluding the answer to ultimate questions like how, when and whether Dimebon might still be an effective N drug for AD patients [12, 13]. In addition, our recent studies showed that Aβ induced mitochondrial perme- abilization is attenuated by Dimebon [14]. The quest of Fig. (1). Structure of Dimebon [78]. understanding molecular mechanisms/targets that aid mild-to-moderate AD patients [6]. A double blind, pla- Dimebon in boosting AD patients’ cognition proclaims cebo-controlled phase II trial with pre-selected mild-to- the need to explore Dimoben’s action in terms of stabi- moderate AD patients showed significant clinical im- lization of energy balance, modulation of cell clearance provements in cognition assessed by AD cooperative systems, and activation of innate defense mechanism. study-activities of daily living (ADL) as a measure of Earlier studies have shown Dimebon as an inhibitor self care and function, and AD assessment scale on of AchE and BchE [15], blocker of L-type Ca2+ chan- cognitive subscale tests with respect to baseline [7]. nels [16], weak competitive agonist of NDMAR [17], However, the phase III trial on a heterogeneous popula- positive modulator of AMPA receptor [18], and have a tion exhibiting multiple neuropathies (with non-AD high affinity for serotonin 5-HT6 and 5-HT7 receptors symptoms as well) failed to reciprocate the promising [19].. Recent studies have shown that Dimebon lowers findings of phase II trials [8]. Both phase II and III tri- formation and subsequent accumulation of pathological als included the dynamics of deterioration of patients’ proteins [20-25], initiate autophagy [26-29], and stabi- health, recruitment age and use of Dimebon formula- lizes mitochondrial functions by blocking permeability tion, thus making it really tough to understand the re- transition [14, 30-33], thus clearly showing its in- markable distinctions between these two trials. Certain volvement in multiple mechanisms of action (Table 1). discrepancy between the results in clinical trials II and Some new findings also suggest that Dimebon could be III was addressed by Bharadwaj et al [9]. The authors used for potential treatment of ischemia, anxiety and argue that phase III failure could be due to either poor depression [34, 35]. All the above discussed data heav- drug efficacy or lack of trial optimization leading to ily support the re-evaluation of therapeutic significance difficulties in interpreting the results. However, it is of Dimebon, so as to position the newly designed ana- worth mentioning that the results in phase II AD study logs as promising therapeutic agents for NDDs [9, 36]. were reflected by overall improvements in Dimebon group and worsening in placebo group; yet, in phase ROLE OF DIMEBON IN NEUROBLASTOMA III, patients in either group did not significantly dete- CELL LINE SH-SY5Y riorate implying the heterogeneous and diverse patho- A transactive response binding protein 43 kDa logical features in each cohort. Moreover, parameters (TDP-43) is the major component of inclusions in FTD such as Dimebon formulation, age of the recruited pa- and ALS patients [37-40]. The ubiquitin-positive intra- tients (mean age of 68.1 and 74.4 years in phase II and cytoplasmic deposits in nerve and glial cells cause III, respectively), and Baseline Mini Mental State Ex- pathological conditions and inevitable neuronal dam- amination (MMSE) were also altered, thus suggesting age. As a result, we proposed that protection effect that phase III results cannot be interpreted in terms of from Dimebon treatment might be due to its inhibitory drug efficacy. This observation calls for new and alter- effect on formation of deposits. To test this hypothesis, native ways of assaying these findings. Also, the failure we used human neuroblastoma cell line SH-SY5Y with of possible Dimebon protective effects on clinical trials two distinct overexpressing pathological isoforms – a might be due to insufficient knowledge about its TDP-43 mutant lacking nuclear localization signal and mechanism of action. Hence, novel studies are required residues 187–192 or another TDP-43 mutant lacking to establish the effect of Dimebon on N-methyl-D- the C-terminal fragment (162–414) fused with green aspartic acid receptor (NMDAR). In addition, there is a fluorescent protein (GFP) reporter [21]. As a result, need for discovery of affected target proteins as well as Dimebon treatment reduced the formation of TDP-43- Dimebon actions on mitochondria and activation of cell positive deposits in a concentration dependent manner clearance pathways. However, a recent twist in the Dimebon as a Neuroprotective Agent Current Medicinal Chemistry, 2016, Vol. 23, No. 30 3 Table 1. Summary of Dimebon effects recapitulating our current in vitro and in vivo findings. In vivo models Dimebon treatment gamma-synucleinopathy Increased average lifespan of transgenic animals Delay in the development of locomotor and coordination pathology Reduced amyloid deposits in spinal cord gray matter Tauopathy Reduced accumulation of hyperphosphorylated tau in spinal cord Slower decline of motor function compared