Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

Abstract

BackgroundSublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context.MethodsAdult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks.ResultsRamipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats.ConclusionsOur results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and suggest that angiotensin II may participate in maintaining the basal rate of granule cell neurogenesis.

Alterations in the rat forebrain apoptosis following exposure to ionizing radiation

“…In humans, impaired hippocampal plasticity may contribute to chronic cognitive impairment and dementia (Abayomi 2002). Mitigating radiation damage by application of neuroprotectants preserving neurogenic potential might be a successful strategy for reducing of late delayed effects (Jenrow et al 2010). Moreover, irradiation of mice with a single dose of 15 Gy by gamma rays decreased neurogenesis in the SVZ and subsequently long-term olfactory memory (Lazarini et al 2009).…”

Advances in Mitigation of Injuries from Radiological Terrorism or Nuclear Accidents

“…Such mitigation was first demonstrated in models of renal injury using angiotensin-converting enzyme inhibitors (ACEis) that are commonly used in human beings to treat hypertension and heart disease 46 . Subsequently, the ACEis were also shown to mitigate experimental radiation-induced lung 47 , brain 48 , and cardiac 49 injuries. One of the ACEis, captopril, has now made the leap from bench-to-bedside and has been shown to be effective for mitigation of radiationinduced renal injury in human beings 50 (Fig.…”

“…In the laboratory, a wide range of late normal tissue injuries can be mitigated using therapies that are not started until days to weeks after irradiation 25,[46][47][48][49][50][51][52][53][54] . Such mitigation was first demonstrated in models of renal injury using angiotensin-converting enzyme inhibitors (ACEis) that are commonly used in human beings to treat hypertension and heart disease 46 .…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…There are numerous reports establishing the rat model for studying radiation injury, both of an acute, early arising nature as well as the more chronic, delayed-type injuries, along with complementary studies of various types of radiation countermeasures (Geraci et al 1995;Moulder et al 1998;Williams et al 2010;Jenrow et al 2010;Kma et al 2012;Gao et al 2013). Rats have been used to study radiationinduced pneumonitis and lung fibrosis (Ghosh et al 2009;Gao et al 2012).…”