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The brain makes its own marijuana. Of course, no one knew this until recently. Thus, for many thousands of years our ancestors harvested or cultivated marijuana-producing plants in order to experience euphoria, which is the brain's response to the stimulation of its own marijuana neurotransmitter system. Marijuana also has analgesic, i.e., pain relief, and anti-inflammatory effects which may become the basis for its medical use in the future. The discovery of your brain's own marijuana neurotransmitter, called anandamide, has demonstrated how important this neurotransmitter system is to normal brain function. Cannabinoid neurons control the release of dopamine; this action explains the ability of marijuana to produce euphoria. The stimulation of cannabinoid function in your brain's feeding centers may underlie the classic side-effect known as “the munchies.” Once again, it can be seen that understanding the distribution of a neurotransmitter in the brain provides clues to its function and insight into why we consume certain plants.

Contrary to a long-held dogma, neurogenesis occurs throughout adulthood in mammals, including humans. Neurogenesis occurs primarily in two regions of the adult brain, the hippocampus and the subventricular zone (SVZ), along the ventricles. Neural progenitor and stem cells have been isolated from various regions of the adult central nervous system (CNS) and characterized in vitro, providing evidence that neural stem cells reside in the adult CNS and are potential sources of tissue for therapy. Adult neurogenesis is modulated in animal models and patients with neurological diseases and disorders, such as Alzheimer's disease, depression, and epilepsy. The contribution of adult neurogenesis to neurological diseases and disorders, and its significance, remains to be elucidated. Cellular therapy may involve the stimulation of endogenous neural progenitor or stem cells and the grafting of neural progenitor and stem cells to restore the degenerated or injured pathways. Mounting evidence suggests that neuroinflammation is involved in the pathogenesis of neurological diseases and disorders.

Multiple sclerosis (MS) is considered an autoimmune chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. The view of MS as a “two-stage disease”, with a predominant inflammatory demyelination in the early phase (relapsing-remitting MS form) and a subsequent secondary neurodegeneration in the early phase (secondary or primary progressive MS) of the disease, is now challenged by the demonstration that axonal destruction may occur independently of inflammation and may also produce it. Therefore, as CNS inflammation and degeneration can coexist throughout the course of the disease, MS may be a “simultaneous two-component disease”, in which the combination of neuroinflammation and neurodegeneration promotes irreversible disability. This chapter discusses factors that contribute to the pathogenesis of MS, immune surveillance in the CNS, regulation of immune responses in the inflamed CNS, initiation of T helper 1 (Th1)-mediated immune reactions in the inflamed CNS, amplification of Th1-mediated immune responses in inflamed CNS and tissue damage, and development of autoimmunity in MS.

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are not well understood. Potential mechanism underlying functional recovery after brain ischemia in aged subjects include neuroinflammation, changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Studies suggest that behaviorally, aged rats were more severely impaired by ischemia than were young rats and showed diminished functional recovery. Both in old and young rats, the early intense proliferative activity following stroke leads to a precipitous formation of growth-inhibiting scar tissue, a phenomenon amplified by the persistent expression of neurotoxic factors. Recent evidence shows that the human brain can respond to stroke with increased progenitor proliferation in aged patients, opening the possibilities of utilizing this intrinsic attempt for neuroregeneration of the human brain as a potential therapy for ischemic stroke.

In vivo markers of microglial activation such as ¹¹C-PK11195 PET can provide a measure of ongoing neurodegeneration in patients with PD and other parkinsonian syndromes. The spatial distribution of microglial activation revealed by PET studies using this approach is concordant with known patterns of histopathological change involving the substantia nigra, striatum and nucleus basalis, and in the cingulate and temporal cortex of non-demented patients. The chapter reviews how these findings are substantiated in vivo with ¹¹C-PK11195 PET, pointing to widespread brain involvement early in the clinical course of the disease. The chapter also discusses the potential impact of neuroimaging investigations on the role of microglial activation in PD on drug development, as well as applications to the pathophysiology of PD and atypical forms of parkinsonism.

In the avian brain, aromatase is constitutive and inducible in neurons and glia respectively. Glial aromatase is rapidly and dramatically upregulated in astroglia (astrocytes and radial glia) independent of brain region, in response to perturbation of the neuropil. Estrogens, synthesized by induced aromatization in glial cells, are potent mitigators of apoptotic degeneration and may accelerate neuronal replacement following brain damage. Specifically, aromatase inhibition increases, and estradiol replacement decreases secondary degeneration at the site of primary damage in the passerine brain. Indeed, the characteristic wave of secondary degeneration observed in mammals following compromise of the brain, is severely dampened in the passerine brain and is only revealed following inhibition of inducible glial aromatization. Further, the rate of injury-induced neurogenesis is increased in birds receiving estradiol replacement relative to those treated with an aromatase inhibitor alone. This chapter reviews data on the structural and functional consequences of glial aromatization. It highlights emerging data on the signals that invariably accompany brain damage and their potential role as inductive signals for the transcription and translation of the aromatase gene specifically in glial cells. The robust and cell-specific expression of aromatase in the passerine brain continues to provide an excellent model for the study of the provision of estrogens to neural targets with temporal and spatial specificity. In addition to basic scientific questions, passerine songbirds may serve as superb animal models toward understanding clinical syndromes involving brain damage, ischemia/anoxia, and neurodegeneration.

This chapter on estrogenic regulation of glia and neuroinflammation reviews the role of glial cells in the modulation of synaptic function under physiological conditions and in the regulation of the neuroinflammatory response under pathological conditions. The anti-inflammatory actions of estradiol on astrocytes, oligodendrocytes, and microglia and the implication of these actions for the neuroprotective and tissue repair effects of the hormone are also discussed. Finally, the therapeutic potential of synthetic and natural estrogenic compounds for the control of neuroinflammation is examined. Because reducing neuroinflammation prevents the progressive loss of neural structure and function that leads to functional and mental impairments, regulation of glial cell activation via estradiol is a promising therapeutic approach.