Benzodiazepines (BZDs) are a widely used class of sedative and anti-anxiety medications, and their usage increases with age (NIH news, 2014). While BZDs are powerfully effective for treating hyper-excitatory disorders, they can have serious side effects, such as motor deficits. The vast majority of elderly BZD users stays in BZD therapy for a prolonged period (NIH news, 2014), which exacerbates the motoric deficits. The adverse effects and long-term use of BZD are seen more in elderly women than other age/gender population groups. However, how chronic BZD (cBZD) usage impairs the motoric function of elderly women remains virtually unknown. The objective for this proposal is to establish a transgenic mouse model that is capable of identifying the mechanism by which cBZD induces motoric aging in female subjects. BZD binds to the GABA- BZD receptor complex, thereby eliciting CNS depressant effects. It is also well known that BZDs including diazepam, lorazepam, and alprazolam, bind to mitochondrial BZD receptors (mBZD-R), located in mitochondrial membranes. The excessive stimulation of mBZD-R damages mitochondrial membranes where mitochondrial respiration takes place, consequently overproducing reactive O2 species (ROS). The binding of BZD to mBZD-R was significantly increased in the cerebellum of the elderly with cognitive disorders (Yasuno et al., 2012), suggesting that mBZD-R plays a role in brain aging. In particular, mBZD-R activity involves pro- apoptotic protein p38 such that a p38 inhibitor attenuates the apoptosis induced by mBZD-R ligands (Sutter et al., 2004). Since ROS activates p38 by phosphorylation, the apoptotic effect of p38 would be more severe in elderly women who lack 17-estradiol (E2), which directly scavenges ROS. Purkinje cells are major cerebellar neurons that are particularly vulnerable to apoptotic p38 (see Approach, Guan et al., 2005). Purkinje neurons show an age-dependent accumulation of p38 in a manner that is mitigated by E2 (Jung et al., 2011). We have generated mice that lack p38 in Purkinje neurons, and observed that these mice are more resistant to cBZD- induced motoric deficit and mitochondrial respiratory suppression than wild-type mice. This protective effect of Purkinje p38 downregulation is more prominent in female mice than male mice, suggesting that a female hormone, especially E2, may play a role in that protection. These observations suggest that cBZD provokes an adverse interaction between the mBZD-R and p38 at an E2-deficient age, resulting in Purkinje apoptosis and motoric aging. We will pursue our objective by achieving Specific Aim 1: Determine the mechanism by which cBZD induces motoric aging. We will test a two-step hypothesis: 1A) cBZD's binding to mBZD-R age- dependently suppresses mitochondrial respiration and 1B) cBZD induces Purkinje neuronal apoptosis and motoric deficit through ROS-activated p38 at an E2-deficient age. The proposed research is absolutely critical because it is expected to establish a solid model and foundational mechanism that will be a first step toward lessening the motoric deterioration of elderly women receiving cBZD.

Public Health Relevance

A long-term use of benzodiazepines (BZDs) is prevalent in elderly women and has been reported to impede motoric function and the quality of life. However, how to minimize the aging like effects of BZDs use in elderly women is virtually unexplored. The proposed research is directly relevant to public health because it will establish an animal model targeting cerebellar neurons to study the underlying mechanism as a first step toward lessening the problem.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG053974-02
Application #
9357485
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
St Hillaire-Clarke, Coryse
Project Start
2016-09-30
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Texas
Department
Other Health Professions
Type
Graduate Schools
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107