Although the exact mechanism(s) of radiation-induced brain injury, including cognitive impairment is unclear, potential therapeutic strategies to prevent radiation-induced brain injury include ROS scavengers, anti-inflammatory agents, and NSC transplantation. ROS scavengers have received little attention because they are likely to protect brain tumors to the same extent as they protect normal brain. Thus, most of the preclinical investigations have focused on anti-inflammatory agents and fetal NSC transplantation.
Several rodent studies designed to prevent or ameliorate radiation-induced cognitive impairment have shown promise using anti-inflammatory peroxisome proliferator-activated (PPAR) agonists (Figure
) that have been given to patients for years to treat other syndromes (Derosa, 2010
; McKeage and Keating, 2011
). PPARα, δ, and γ are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that heterodimerize with the retinoid X receptor to regulate gene expression (Blumberg and Evans, 1998
). A growing body of evidence suggests that PPARs regulate inflammatory signaling and are neuroprotective in a variety of CNS diseases (Bright et al., 2008
; Stahel et al., 2008
; Ramanan et al., 2010
). Administering the PPARγ agonist, pioglitazone (Pio), to young adult male rats starting 3 days prior to, during, and for 4 or 54 weeks after the completion of a total 40 Gy dose of fWBI delivered twice a week for 4 weeks, prevented the radiation-induced cognitive impairment measured 52 weeks after fWBI (Figure
; Zhao et al., 2007b
). However, administration of Pio for 54 weeks starting after the completion of fWBI did not significantly modulate radiation-induced cognitive impairment. Based on these data, a phase I/II trial has been initiated to determine the dose of Pio that can be given safely to brain tumor patients and obtain preliminary data on the ability of Pio to prevent/ameliorate radiation-induced cognitive impairment.
FIGURE 6 Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months (more ...)
The renin–angiotensin system (RAS) has been classically viewed as a complex systemic hormonal system. More recently, several intra-organ RAS have been identified, including a brain RAS (Davisson, 2003
). The brain RAS is involved in modulation of the BBB, stress, memory, and cognition (Gard, 2002
; McKinley et al., 2003
). Both angiotensin-converting enzyme inhibitors (ACEI) or angiotensin type-1 receptor blockers (ARB) have proven effective in treating experimental radiation nephropathy (Moulder et al., 2003
) and pneumopathy (Molteni et al., 2000
Chronic administration of the ACEI, ramipril to young adult male F344 rats 2 weeks after stereotactic irradiation of the rat brain with a single dose of 30 Gy was associated with a reduction in the severity of functional and histopathologic markers of optic neuropathy assessed 6 months post-irradiation (Kim et al., 2004
). However, delaying the start of ramipril treatment to 4 weeks after irradiation resulted in a failure to reduce the severity of the radiation injury (Ryu et al., 2007
). More recent studies by Jenrow et al. (2010)
have shown that ramipril produced modest protection against WBI-induced decreases in neurogenesis, but did not modulate radiation-induced neuroinflammation measured as microglial activation. In contrast, a recent study found that ramipril was able to ameliorate both radiation-induced cognitive impairment (Figure
) and microglial activation in rats after fWBI, but had no restorative effect on neurogenesis (Lee et al., 2012
). In the Jenrow et al. (2010)
study, ramipril was started 24 h after a single dose of WBI, whereas drug was administered before, during, and after fWBI in the Lee et al. study. Thus, the timing of the ramipril administration and/or the response after single or fractionated doses may explain the different results obtained in the two studies. At the present time, a phase I/II trial is being developed to determine if ramipril can prevent/ameliorate radiation-induced cognitive impairment in brain tumor patients.
Chronic administration of the ARB, L-158,809, to young adult male rats for 3 days before, during, and for 28 or 54 weeks after fWBI prevented the radiation-induced cognitive impairment observed 26 and 52 weeks post-irradiation (Figure
; Robbins et al., 2009
). Moreover, chronic administration of L-158,809 for 3 days before, during, and only 5 weeks post-irradiation prevented the cognitive impairment observed 26 weeks post-irradiation (Robbins et al., 2009
). These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks post-irradiation (Robbins et al., 2009
). Thus, both PPARγ agonists and ARBs may prevent/ameliorate radiation-induced cognitive impairment when given for only a few weeks after fWBI.
In addition to drug therapeutics, there has been increased interest in the use of various stem cell therapies to restore the neurogenic niche and improve cognition. These studies are based on the rationale that radiation results in a dramatic reduction in hippocampal neurogenesis that has been linked to cognitive impairment (Raber et al., 2004
; Rola et al., 2004
). Voluntary running has been shown to increase neurogenesis in the rodent hippocampus with a concomitant improvement in spatial learning and memory after single WBI doses (Naylor et al., 2008
; Wong-Goodrich et al., 2010
). Preclinical studies have also shown that pretreatment with lithium or other Akt/glycogen synthase kinase-3β (GSK-3β) inhibitors are neuroprotective, preventing (i) apoptosis in the subgranular zone of the DG and (ii) the radiation-induced decline in hippocampal dependent memory in 1-week-old mice that received a single dose of 7 Gy WBI (Yazlovitskaya et al., 2006
; Thotala et al., 2008
). Direct injection of NSCs into rodent brains after WBI partially restores neurogenesis and hippocampal-dependent cognitive function (Acharya et al., 2009
; Joo et al., 2012
). Interestingly, these NSCs not only differentiate into neurons, but also oligodendrocytes, astrocytes, and endothelial cells that can alter the hippocampal microenvironment (Joo et al., 2012
). However, the use of exercise or NSC transplantation to prevent/ameliorate radiation-induced cognitive impairment in humans will require considerably more research before it can be translated to the clinic.
CLINICAL STUDIES OF THERAPEUTIC INTERVENTIONS FOR RADIATION-INDUCED BRAIN INJURY
One strategy for the prevention of radiation-induced cognitive impairment in the clinic involves avoidance of brain structures associated with cognitive function. Recent clinical trials have focused on avoiding the regions of adult neurogenesis, including the hippocampus and neural stem cell niche in the periventricular regions. These trials have been met with criticism because NSCs, like the stem cells found in other organ systems, are thought to be exquisitely sensitive to ionizing radiation; complete elimination of the NSCs in rodents occurs in the range of 2–6 Gy (Barani et al., 2007a
; Gutiérrez et al., 2007
). In addition, other brain regions such as the dorsal lateral prefrontal cortex play a major role in human cognition, unlike in the rodent where the hippocampus dominates. Preliminary data from the University of Wisconsin suggest that patients receiving doses ≥7.2 Gy to the bilateral hippocampi have worse cognitive function as measured by the Wechsler Memory test (Gondi et al., 2011
). The RTOG is currently conducting a single arm prospective trial using hippocampal-sparing IMRT. This trial intends to enroll 100 patients and assess cognitive outcomes compared to historical controls. While technology has evolved to potentially allow for hippocampal sparing, it may be premature to conduct large-scale prospective clinical trials for hippocampal sparing when brain regions other than the hippocampus are involved in cognition, and the dose that eliminates neurogenesis in the human hippocampus is unknown.
There are no known preventive medications for radiation-induced cognitive impairment in humans, although several pharmacologic agents have been evaluated for symptomatic management. The first category of drugs assessed were the psychostimulants. There are several reports (DeLong et al., 1992
; Weitzner et al., 1995
; Meyers et al., 1998
) using methylphenidate to treat radiation-induced fatigue and cognitive impairment. Using methylphenidate doses of 10-30mg twice daily in adults, fatigue is reduced and cognitive function is enhanced. Another class of drugs are the reversible cholinesterase inhibitors such as donepezil (Aricept®
). The Wake Forest Community Clinical Oncology Program Research Base recently completed a clinical trial randomizing 200 brain tumor patients who survived at least 6 months after fractionated partial- or whole-brain irradiation to either placebo or donepezil 10 mg/day for 6 months. The randomized trial was based on results of a previously completed phase II open-label study where 10 mg/day of donepezil showed significant improvement in energy level, mood, and cognitive function in an identical patient population or irradiated brain tumor survivors (Shaw et al., 2006
). In the phase II study, fatigue, mood, and cognition were also measured following a 6-week washout period from the discontinuation of donepezil. Worsening in all three domains was observed.
The RTOG has just completed a randomized placebo controlled trial evaluating the efficacy of memantine, an NMDA receptor antagonist that has been shown to be effective in vascular dementia. It is hypothesized that blocking this receptor blocks ischemia-induced NMDA excitation and thus, may be neuroprotective if radiation-induced ischemia occurs after fWBI. In this study, patients were treated with either memantine or placebo during and for 24 weeks after fWBI. The primary endpoint of the study involves memory deficits measured by the Hopkins Verbal Learning Test at 24 weeks. The trial has 554 patients and is now closed to accrual; to date, there are no preliminary results.
Finally, clinical trials of other potential pharmacological mediators of cognitive function are being developed based on preclinical data suggesting that anti-inflammatory agents can prevent or ameliorate radiation-induced cognitive function. A phase I/II trial of Pio given to brain tumor patients before, during, and after fWBI has been initiated, and phase I/II trials of ramipril and an ARB are being developed. Although it is simplistic to think that one approach or one pharmacological intervention will eliminate radiation-induced brain injury, including cognitive impairment for every patient whose brain is treated with ionizing radiation, it is highly likely that significant inroads will be made to prevent/ameliorate this increasingly important side effect of brain irradiation over the next decade.