3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride protects against 6‐hydroxydopamine‐induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats

Abstract

To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), a functionally selective α7 nAChR agonist, in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. Microinjection of 6-OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6-OHDA-induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6-OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6-OHDA-induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development.

Intravenous mesenchymal stem cell administration exhibits therapeutic effects against 6-hydroxydopamine-induced dopaminergic neurodegeneration and glial activation in rats

“…Remediation of PD by dopamine replacement therapy, which has been used mainly for ameliorating movement disturbances in PD, does not prevent progression. Many neuroprotective compounds have been tested in PD models, but most were administered before or at the same time as lesioning [17,21].…”

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

“…The improvement is associated with a SNP (rs3087454) in the 5′-upstream regulatory region of the CHRNA7 gene, previously associated with schizophrenia (Table 2) (Stephens et al, 2009). DMXB-A may also be useful in Parkinson’s disease in a neuroprotective role (Suzuki et al, 2013). …”

The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions

“…For instance, nicotine protects against glutamate-, ethanol-, NMDA-, oxygen-deprivation- and β-amyloid-induced cytotoxicity in different neuronal culture systems via α7 nAChRs (Dajas-Bailador et al, 2000; de Fiebre and de Fiebre, 2003; Kaneko et al, 1997; Li et al, 2000; Rosa et al, 2006; Toulorge et al, 2011; Wang et al, 2000). In addition, work in parkinsonian animal models show that drugs such as the α7 nAChR allosteric modulator galantamine or the relatively selective α7 agonist DMXB protect against 6-OHDA-induced nigrostriatal damage in rats (Suzuki et al, 2013; Yanagida et al, 2008), while the α7 agonist PNU-282987 attenuated MPTP-induced nigrostriatal damage in mice (Stuckenholz et al, 2013). …”