Kosyakovsky Jacob, Fine Jared M, Frey William H, Hanson Leah R
School of Medicine, University of Virginia, 200 Jeanette Lancaster Way, Charlottesville, VA 22903, USA.
HealthPartners Neuroscience Center, HealthPartners Institute, Saint Paul, MN 55130, USA.
Pharmaceuticals (Basel). 2021 Jan 27;14(2):95. doi: 10.3390/ph14020095.
Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.
确定针对神经疾病的疾病修饰疗法仍然是现代医学中最大的差距之一。在此，我们阐述了将去铁胺（DFO，一种高亲和力铁螯合剂）经鼻内（IN）给药作为治疗神经退行性和神经血管疾病的基本原理，重点关注其新机制。脑铁稳态失衡伴铁蓄积是脑衰老的一个已知特征，并且与多种神经疾病的发病机制有关。大量临床前证据和早期临床数据表明，经鼻内给予DFO和其他铁螯合剂在阿尔茨海默病（AD）、帕金森病（PD）、缺血性中风和颅内出血（ICH）中具有强大的疾病修饰作用。DFO通过铁螯合这一疾病非特异性途径，通过多因素机制针对这些复杂疾病中的每一种。越来越多的证据表明，经鼻内给予DFO在认知衰老、多发性硬化症、创伤性脑损伤、其他神经退行性疾病和血管性痴呆中可能还有其他有益机制。考虑到其已知的安全性、靶向给药方法、强大的临床前疗效、多种机制以及在许多神经疾病中的潜在适用性，进一步开发经鼻内给予DFO的理由很充分。
