Zonisamide Attenuates α-Synuclein Neurotoxicity by an Aggregation-Independent Mechanism in a Rat Model of Familial Parkinson’s Disease

Abstract

The anti-epileptic agent zonisamide (ZNS) has been shown to exert protective effects in neurotoxin-based mouse models of Parkinson disease. However, it is unknown whether ZNS can attenuate toxicity of familial Parkinson’s disease-causing gene products. In this study, we investigated the effects of ZNS on neurodegeneration induced by expression of A53T α-synuclein in the rat substantia nigra using a recombinant adeno-associated virus vector. Expression of A53T α-synuclein yielded severe loss of nigral dopamine neurons and striatal dopamine nerve terminals from 2 weeks to 4 weeks after viral injection. Oral administration of ZNS (40 mg/kg/day) significantly delayed the pace of degeneration at 4 weeks after viral injection as compared with the vehicle group. This effect lasted until 8 weeks after viral injection, the final point of observation. ZNS treatment had no impact on the survival of nigrostriatal dopamine neurons in rats expressing green fluorescent protein. Quantification of striatal Ser129-phosphorylated α-synuclein-positive aggregates showed that these aggregates rapidly formed from 2 weeks to 4 weeks after viral injection. This increase was closely correlated with loss of nigrostriatal dopamine neurons. However, ZNS treatment failed to alter the number of all striatal Ser129-phosphorylated α-synuclein-positive aggregates, including small dot-like and large round structures. The number of these aggregates was almost constant at 4 weeks and 8 weeks after viral injection, although ZNS persistently prevented loss of nigrostriatal dopamine neurons during this period. Also, ZNS treatment did not affect the number of striatal aggregates larger than 10 µm in diameter. These data show that ZNS attenuates α-synuclein-induced toxicity in a manner that is independent of the formation and maturation of α-synuclein aggregates in an in vivo model of familial Parkinson’s disease, suggesting that ZNS may protect nigrostriatal dopamine neurons by modulating cellular damage or a cell death pathway commonly caused by neurotoxins and α-synuclein.

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

“…Both of them are pivotal players in DA signaling. A significant negative correlation was found between TH and DAT expression and motor impairment3132. TH and DAT levels were significantly decreased in the brainstem of A53T α-synuclein mice compared with those of the WT littermates, whereas W20, not PBS or ns-scFv, remarkably increased TH and DAT levels in PD transgenic mice (Fig.…”

“…TH is the limiting enzyme in DA synthesis32, whereas DAT is a plasma membrane glycoprotein expressed in DA cells, responsible for DA uptake through a Na + /Cl − coupled cotransport mechanism33. Both of them are pivotal players in DA signaling.…”

“…TH is a rate-limiting enzyme involved in DA generation, while DAT is expressed in striatal presynaptic terminals and is a major determinant of DA homeostasis. TH and DAT levels are inversely correlated with the total α-synuclein burden in the substantia nigra of PD patients or animal models3246. W20 increased levels of TH and DAT in the brainstem of A53T α-synuclein mice by decreasing α-synuclein levels, protecting neuronal cells from degeneration, thus leading the improvement of motor and cognition performances.…”

A comparative trial of selegiline and zonisamide for disease modifying effects on DAT-SPECT in patients with Parkinson’s disease: study protocol for a prospective multicenter randomized study (DATSZ-PD study)

“…Zonisamide has been shown to improve motor function in Parkinson's disease [12]. It is also a candidate drug for disease-modifying therapy because of its protective action on dopamine neurons shown in non-clinical studies [13][14][15][16][17][18].…”

Estudo dos efeitos da superexpressão da alfa-sinucleína sobre o tráfego mitocondrial e autofagia em leveduras, células SH-SY5Y e neurônios dopaminérgicos derivados de hiPSC de pacientes com doença de Parkinson

“…In contrast, others studies showed that oligomers of alpha-synuclein (preaggregates) are more toxic than aggregates (Kaufmann et al, 2016;Lam et al, 2016;Deas et al, 2016;Lorenzen and Otzen 2014). In addition, it has been suggested that aggregate formation is a protective mechanism to prevent cell death (Mahul-Mellier et al, 2015;Arawaka et al, 2014;Danzer and McLean, 2011;Kaganovich et al, 2008).…”